Novel derivatives of benzimidazole and imidazo-pyridine and their use as medicaments

ABSTRACT

A subject of the present Application is novel derivatives of benzimidazole and imidazopyridine which have a good affinity for certain sub-types of melanocortin receptors, in particular the MC4 receptors. They are particularly useful for treating pathological conditions and diseases in which one or more melanocortin receptors are involved. The invention also relates to pharmaceutical compositions containing said products.

A subject of the present Application is novel derivatives ofbenzimidazole and imidazopyridine. These products have a good affinityfor certain sub-types of melanocortin receptors, in particular the MC4receptors. They are particularly useful for treating pathologicalconditions and diseases in which one or more melanocortin receptors areinvolved. The invention also relates to pharmaceutical compositionscontaining said products and their use for preparing a medicament.

The melanocortins represent a group of peptides which derive from thesame precursor, proopiomelanocortin (POMC), and which are structurallyclose: the adrenocorticotropic hormone (ACTH), the α-melanocytestimulating hormone (α-MSH), β-MSH and γ-MSH (Eipper B. A. and Mains R.E., Endocr. Rev. 1980, 1, 1-27). The melanocortins carry out numerousphysiological functions. They stimulate the synthesis of the steroids bythe adrenal cortex and the synthesis of eumelanine by the melanocytes.They regulate the intake of food, energetic metabolism, sexual function,neuronal regeneration, blood pressure and heart rate, as well as theperception of pain, learning, attention and memory. The melanocortinsalso possess anti-inflammatory and anti-pyretic properties and controlthe secretion of several endocrine or exocrine glands such as thesebaceous, lacrimal and mammary glands, the prostate and the pancreas(Wikberg J. E. et al. Pharmacol. Res. 2000, 42, 393-420; Abdel-Malek Z.A., Cell. Mol. Life. Sci. 2001, 58, 434-441).

The effects of the melanocortins are mediated by a family of membranereceptors specific to seven transmembrane domains and coupled to Gproteins. Five sub-types of receptors, named MC1 to MC5, have beencloned and characterized to date. These receptors differ in their tissuedistribution and in the affinity of different melanocortins, the MC2receptors only recognizing the ACTH. The stimulation of the melanocortinreceptors activates adenylate cyclase with production of cyclic AMP. Ifthe specific functional roles of each of the receptors are not totallyelucidated, the treatment of pathological disorders or diseases can beassociated with an affinity for certain sub-types of receptors. Thusactivation of the MC1 receptors has been associated with the treatmentof inflammations, while blocking them has been associated with thetreatment of cutaneous cancers. The treatment of nutritional disordershas been associated with the MC3 and MC4 receptors, the treatment ofobesity with agonists and the treatment of cachexia and anorexia withantagonists. Other indications linked to the activation of the MC3 andMC4 receptors are problems with sexual activity, neuropathic pain,anxiety, depression and drug addiction. The activation of the MC5receptors has been associated with the treatment of acne and dermatoses.

The Applicants have discovered that the novel compounds of generalformula (I) described hereafter possess a good affinity for themelanocortin receptors. They preferably act on the MC4 receptors. Saidcompounds, agonists or antagonists of the melanocortin receptors, can beused for treating the pathological conditions or diseases of themetabolism, of the nervous system or dermatological diseases in whichone or more melanocortin receptors are involved such as the followingexamples: inflammatory conditions, energetic homeostasis disorders,intake of food disorders, weight disorders (obesity, cachexia,anorexia), sexual activity disorders (erective disorders), pain and moreparticularly neuropathic pain. Mental health problems (anxiety,depression), drug addiction, skin diseases (acne, dermatoses, skincancer, melanomas) can also be mentioned. These compounds can also beused to stimulate nerve regeneration.

A subject of the invention is therefore a compound of general formula(I)

in racemic or enantiomeric form or any combinations of these forms andin which:A represents —CH₂—, —C(O)—, —C(O)—C(R_(a))(R_(b))—;X represents —CH— or —N—;R_(a) and R_(b) represent, independently, the hydrogen atom or a(C₁-C₆)alkyl radical;R₁ represents the hydrogen atom; a (C₁-C₈)alkyl radical optionallysubstituted by hydroxy or one or more identical or different haloradicals; (C₂-C₆)alkenyl; or a radical of formula —(CH₂)_(n)—X₁;R₂ represents a (C₁-C₈)alkyl radical optionally substituted by hydroxyor one or more identical or different halo radicals; (C₂-C₆)alkenyl; ora radical of formula —(CH₂)_(n)—X₁;each X₁ independently represents (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,adamantyl, heterocycloalkyl, aryl or heteroaryl,

-   -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n′)—V₁—Y₁ halo,        nitro, cyano and aryl;    -   V₁ represents —O—, —S— or a covalent bond;    -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals;    -   n represents an integer from 0 to 6 and n′ an integer from 0 to        2 (it being understood that when n is equal to 0, then X₁ does        not represent the alkoxy radical);        or R₁ and R₂ form together with the nitrogen atom to which they        are attached, a heterobicycloalkyl or a heterocycloalkyl        optionally substituted by one or more identical or different        substituents chosen from: hydroxy, (C₁-C₆)alkyl optionally        substituted by hydroxy, (C₁-C₆)alkoxy-carbonyl, heterocycloalkyl        and —C(O)NV₁′Y₁′ with V₁′ and Y₁′ independently representing the        hydrogen atom or a (C₁-C₆)alkyl; or R₁ and R₂ together form a        radical of formula:

R₃ represents -Z₃, —C(R_(Z3))(R′_(Z3))-Z₃,—C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ or —C(O)-Z′₃

-   -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z₃ represents Z_(3a), Z_(3b), Z_(3c), Z_(3d), or Z_(3e);    -   Z_(3a) represents a (C₁-C₆)alkyl radical;    -   Z_(3b) represents a (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,        (C₁-C₆)alkylamino or di((C₁-C₆)alkyl)amino radical;    -   Z_(3c) represents an aryl or heteroaryl radical;    -   Z_(3d) represents a (C₁-C₆) alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkylamino-carbonyl, di((C₁-C₆)alkyl)amino-carbonyl,        (C₁-C₆)alkyl-C(O)—NH—, (C₃-C₇)cycloalkyl, heterocycloalkyl        radical;    -   the (C₃-C₇)cycloalkyl and heterocycloalkyl radicals being        optionally substituted by one or more identical or different        substituents chosen from: halo, nitro, (C₁-C₆)alkoxy optionally        substituted by one or more identical or different halo radicals,        (C₁-C₆)alkyl optionally substituted by one or more identical or        different halo radicals, (C₁-C₆)alkyl-carbonyl,        (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkylamino-carbonyl, di((C-C₆)alkyl)amino-carbonyl and        oxy,    -   the aryl and heteroaryl radicals being optionally substituted by        one or more identical or different substituents chosen from:        halo, cyano, nitro, azido, oxy,        (C₁-C₆)alkoxy-carbonyl-(C₁-C₆)alkenyl,        (C₁-C₆)alkylamino-carbonyl-(C₁-C₆)alkenyl, —SO₂—NR₃₁R₃₂,        heterocycloalkyl, heteroaryl or —(CH₂)_(p′)—V₃—Y₃;    -   R₃₁ and R₃₂ form together with the nitrogen atom to which they        are attached, a heterocycloalkyl;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —O—C(O)—, —SO₂—,        —SO₂NH—, —NR₁₃—SO₂—, —NR₁₃—, —NR₁₃—C(O)—, —C(O)—NR₁₃—,        —NH—C(O)—NR₁₃— or a covalent bond;    -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals; an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro, (C₁-C₆)alkyl and (C₁-C₆)alkoxy; or an aryl-(C₁-C₆)alkyl        radical optionally substituted by one or more identical or        different substituents chosen from: halo, nitro, (C₁-C₆)alkyl        and (C₁-C₆)alkoxy;    -   Z_(3e) represents a radical of formula

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃—,        —NH—C(O)—NR₁₃— or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;    -   p represents an integer from 1 to 4; p′ and p″ represent,        independently, an integer from 0 to 4;        R′₄ represents a radical of formula —(CH₂)_(s)—R′₄        R′₄ represents the guanidine radical; a heterocycloalkyl        containing at least one nitrogen atom and optionally substituted        by (C₁-C₆)alkyl or aralkyl; a heteroaryl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl optionally        substituted by one or more identical or different substituents        chosen from: (C₁-C₆)alkoxy, (C₁-C₆)alkylthio and hydroxy;        (C₂-C₆)alkenyl; (C₃-C₇)cycloalkyl optionally substituted by one        or more identical or different (C₁-C₆)alkyl substituents;        cyclohexene; heteroaryl and aryl;        -   the aryl and heteroaryl radicals being optionally            substituted by one or more identical or different radicals            chosen of formula: —(CH₂)_(s″)—V₄—Y₄, hydroxy, halo, nitro            and cyano;            -   V₄ represents —O—, —S—, —NH—C(O)—, —NV₄′— or a covalent                bond;            -   Y₄ represents a hydrogen atom or a (C₁-C₆)alkyl radical                optionally substituted by one or more identical or                different halo radicals;            -   V₄′ represents a hydrogen atom or a (C₁-C₆)alkyl;            -   s″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   s and s′ represent, independently, an integer from 0 to 6;        and i) when R₃ represents —C(O)-Z′₃ and R₄ represents a radical        of formula —(CH₂)_(s)—NW₄W₄ and W₄ and W′₄ represent,        independently, the hydrogen atom or the (C₁-C₆)alkyl radical,        then —(CH₂)_(s) represents neither the ethylene radical nor the        —(CH₂)—CH((C₁-C₄)alkyl)-radical and ii) when R₃ represents        -Z_(3c) and Z_(3c) represents a phenyl or naphthyl radical, then        phenyl and naphthyl are not substituted by cyano; and it being        understood that when R₃ represents -Z_(3d) then Z_(3d) only        represents one (C₃-C₇) cycloalkyl or heterocycloalkyl radical;        or a pharmaceutically acceptable salt thereof.

In the definitions given above, the expression halo represents thefluoro, chloro, bromo or iodo radical, preferably chloro, fluoro orbromo. The expression alkyl (unless otherwise specified), preferablyrepresents a linear or branched alkyl radical having from 1 to 6 carbonatoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl,2,2-dimethyl-propyl, hexyl, isohexyl or 1,2,2-trimethyl-propyl radicals.The term (C₁-C₈)alkyl designates a linear or branched alkyl radicalhaving from 1 to 8 carbon atoms, such as the radicals containing from 1to 6 carbon atoms as defined above but also heptyl, octyl,1,1,2,2-tetramethyl-propyl, 1,1,3,3-tetramethyl-butyl. The termhydroxyalkyl designates the radicals in which the alkyl radical is asdefined above such as for example hydroxymethyl, hydroxyethyl. By theexpression alkyl substituted by hydroxy is meant any linear or branchedalkyl chain, containing a hydroxy radical positioned along the chain;thus for a chain containing 3 carbon atoms and one hydroxy radical,HO—(CH₂)₃—, CH₃—CH(OH)—CH₂— and CH₃—CH₂—CH(OH)— can be cited asexamples.

By alkenyl, unless otherwise specified, is meant a linear or branchedalkyl radical containing from 1 to 6 carbon atoms and having at leastone unsaturation (double bond), such as for example vinyl, allyl,propenyl, butenyl or pentenyl.

The term alkoxy designates the radicals in which the alkyl radical is asdefined above such as for example the methoxy, ethoxy, propyloxy orisopropyloxy radicals but also linear, secondary or tertiary butoxy,pentyloxy. The term alkoxy-carbonyl preferably designates the radicalsin which the alkoxy radical is as defined above such as for examplemethoxycarbonyl, ethoxycarbonyl. The term alkylthio designates theradicals in which the alkyl radical is as defined above such as forexample methylthio, ethylthio. The term guanidine represents the—NHC(═NH)NH₂ radical.

The term (C₃-C₇)cycloalkyl designates a saturated carbon monocyclicsystem comprising from 3 to 7 carbon atoms, and preferably thecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.The expression heterocycloalkyl designates a condensed monocyclic orbicyclic saturated system containing from 2 to 9 carbon atoms and atleast one heteroatom. This radical can contain several identical ordifferent heteroatoms. Preferably, the heteroatoms are chosen fromoxygen, sulphur or nitrogen. As an example of a heterocycloalkyl, theremay be mentioned the rings containing at least one nitrogen atom such aspyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine,thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine,azepane (azacycloheptane), azacyclooctane, diazepane, morpholine,decahydroisoquinoline (or decahydroquinoline) but also the rings notcontaining any nitrogen atom such as tetrahydrofuran ortetrahydrothiophene. As an example of cycloalkyl or heterocycloalkylsubstituted by oxy, for example pyrrolidinone and imidazolidinone can bementioned.

The term heterobicycloalkyl designates a non-condensed saturatedhydrocarbon bicyclic system containing from 5 to 8 carbon atoms and atleast one heteroatom chosen from nitrogen, oxygen and sulphur. As anexample of heterobicycloalkyl, aza-bicycloheptane and aza-bicyclooctanesuch as 7-aza-bicyclo[2,2,1]heptane, 2-aza-bicyclo[2,2,2]octane or6-aza-bicyclo[3,2,1]octane can be mentioned.

The expression aryl represents an aromatic radical, constituted by aring or condensed rings, such as for example the phenyl, naphthyl,fluorenyl or anthryl radical. The expression heteroaryl designates anaromatic radical, constituted by a ring or condensed rings, with atleast one ring containing one or more identical or different heteroatomschosen from sulphur, nitrogen or oxygen. As an example of a heteroarylradical, there can be mentioned the radicals containing at least onenitrogen atom such as pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl,pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl, indolyl,dihydroindolyl, benzoxadiazoyl, carbazolyl, phenoxazinyl but also theradicals not containing a nitrogen atom such as thienyl, benzothienyl,furyl, benzofuryl dibenzofuryl, dihydrobenzofuryl, dibenzothienyl,thioxanthenyl, or pyranyl. The term aralkyl (arylalkyl) preferablydesignates the radicals in which the aryl and alkyl radicals are asdefined above such as for example benzyl or phenethyl. As an example ofan aryl or heteroaryl radical substituted by oxy, for examplefluorenone, acridone, xanthenone, benzothienyl-dione, anthraquinone,thioxanthene, benzocoumarine can be mentioned.

In the present Application also, the (CH₂)_(i) radical (i integer beingable to represent n, n′, p, p′, p″, s, s′ and s″ as defined above),represents a linear or branched hydrocarbon chain, with i carbon atoms.Thus the —(CH₂)₃ radical can represent —CH₂—CH₂—CH₂— but also—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)— or —C(CH₃)₂—.

According to the present Application also, when a radical has theformula —B-D-E with D representing for example —C(O)—NH—, this meansthat the carbon atom of —C(O)—NH— is bound to B and the nitrogen atom toE.

Preferably, the invention relates to compounds of formula I as definedabove and characterized in that X represents —CH—; or a pharmaceuticallyacceptable salt thereof.

Preferably, the invention relates to compounds of formula I as definedabove, characterized in that X represents —CH— and A represents —CH₂,and more particularly

-   -   R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;    -   R₃ represents -Z_(3c), —C(R_(Z3))(R′_(Z3))-Z_(3c),        —C(R_(Z3))(R′_(Z3))-Z_(3d),        —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z_(3d);    -   R₄ represents a radical of formula —(CH₂)_(s)—R₁₄;    -   R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄;        -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;        -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;        -   Z₄ represents the hydrogen atom;        -   s represents an integer from 2 to 4; s′ represents an            integer from 0 to 4;            and preferably    -   the heterocycloalkyl represented by R′₄ is the piperidine ring;    -   R_(Z3) and R′_(Z3) represent the hydrogen atom;    -   Z₃, represents the thienyl, furyl or phenyl radical,        -   the phenyl radical being substituted by one or more            identical or different substituents chosen from: halo and            —(CH₂)_(p′)—V₃—Y₃;        -   V₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃— or a            covalent bond;        -   R′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical;        -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical            optionally substituted by one or more identical or different            halo radicals;    -   Z_(3d) represents the (C₁-C₆)alkoxy-carbonyl or heterocycloalkyl        radical, and preferably the heterocycloalkyl is imidazolidine;        or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH— and A represents—C(O)—C(R_(a))(R_(b))— with R_(a) and R_(b) representing the methylradical; and more particularly

-   -   R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;    -   R₃ represents -Z_(3c), —C(R_(Z3))(R′_(Z3))-Z_(3c),        —C(R_(Z3))(R′_(Z3))-Z_(3d) or        —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z_(3d);    -   R₄ represents a radical of formula —(CH₂)_(s)—R₁₄;    -   R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄;        -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;        -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;        -   Z₄ represents the hydrogen atom, the phenyl radical or a            heteroaryl;        -   s represents an integer from 2 to 4; s′ represents an            integer from 0 to 4;            and preferably    -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom;    -   Z_(3c) represents a thienyl radical optionally substituted by        (C₁-C₆)alkoxy-carbonyl; or phenyl substituted by one or more        identical or different substituents chosen from: halo, nitro or        —(CH₂)_(p′)—V₃—Y₃;        -   V₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃— or a            covalent bond;        -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical            optionally substituted by one or more identical or different            halo radicals;        -   R′₃ represents the hydrogen atom;    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl radical;    -   the heterocycloalkyl represented by R′₄ is piperidine;    -   the heteroaryl represented by Z₄ is pyridine; or a        pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH— and A represents—C(O)—,

and more particularly R₃ represents —C(O)-Z′₃;

-   -   R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;    -   Z′₃ represents a phenyl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p′)—V′₃—Y′₃        -   V′₃ represents —O—, —C(O)—O— or a covalent bond;        -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical;        -   p″ represents the integer 0;    -   R₄ represents a radical of formula —(CH₂)_(s)—R′₄ and R′₄        represents a radical of formula —NW₄W′₄        -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;        -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄ and Z₄            represents the hydrogen atom;        -   s represents an integer from 2 to 4; s′ represents an            integer from 0 to 4;            or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH— and A represents—C(O)—, and

-   -   R₁ represents a hydrogen atom, a (C₁-C₈)alkyl radical optionally        substituted by hydroxy, (C₂-C₆)alkenyl or a radical of formula        —(CH₂)_(n)—X₁;    -   R₂ represents a (C₁-C₈)alkyl radical optionally substituted by        hydroxy, (C₂-C₆)alkenyl or a radical of formula —(CH₂)_(n)—X₁;    -   each X₁ represents, independently, (C₁-C₆)alkoxy,        (C₃-C₇)cycloalkyl, aryl or heteroaryl,        -   the aryl radical being optionally substituted by one or more            identical or different substituents chosen from:            —(CH₂)_(n′)—V₁—Y₁, halo;        -   V₁ represents —O— or a covalent bond;        -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted            by one or more identical or different halo radicals; or            aryl;    -   or R₁ and R₂ form together with the nitrogen atom to which they        are attached, a heterocycloalkyl optionally substituted by one        or more identical or different substituents chosen from:        hydroxy, (C₁-C₆)alkyl optionally substituted by hydroxy,        (C₁-C₆)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV₁′Y₁′ with        V₁′ and Y₁′ independently representing the hydrogen atom or a        (C₁-C₆)alkyl,    -   or R₁ and R₂ together form a radical of formula:

-   -   R₃ represents -Z₃, —C(R_(Z3))(R′_(Z3))-Z₃ or        —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃;    -   R₄ represents a radical of formula —(CH₂)_(s)—R′₄    -   R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl or        aralkyl; a heteroaryl containing at least one nitrogen atom and        optionally substituted by (C₁-C₆)alkyl; or a radical of formula        —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₃-C₇)cycloalkyl or aryl;    -   s represents an integer from 0 to 5; s′ represents an integer        from 0 to 4;        and more particularly characterized in that they have at least        one of the following characteristics:    -   the (C₃-C₇)cycloalkyl radical represented by X₁ is cyclopropyl;    -   the aryl radical represented by X₁ the phenyl radical;    -   the heteroaryl radical represented by X₁ is pyridine;    -   the heterocycloalkyl that R₁ and R₂ form together with the        nitrogen atom to which they are attached is chosen from:        pyrrolidine, piperidine, azepane, azacyclooctane, morpholine,        piperazine and decahydroisoquinoline;    -   the heterocycloalkyl radical represented by R₁₄, optionally        substituted by C₁-C₆)alkyl or benzyl, is chosen from:        pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl;    -   the heteroaryl radical represented by R′₄ is the imidazolyl        radical;    -   the cycloalkyl represented by Z₄ is chosen from: cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;    -   the aryl represented by Z₄ is phenyl; or a pharmaceutically        acceptable salt thereof.

Very preferably, the invention relates to compounds of formula I asdefined above, characterized in that R₄ represents a radical of formula—(CH₂)_(s)—R′₄ with R′₄ representing the pyrrolidinyl or piperidinylradical; or a radical of formula —NW₄W′₄

-   -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄ with Z₄        representing the hydrogen atom;    -   s represents an integer from 2 to 4; s′ represents an integer        from 0 to 4; or a pharmaceutically acceptable salt thereof.

Very preferably also, the invention relates to compounds of formula I asdefined above, characterized in that R₁ and R₂ represent, independently,a (C₁-C₈)alkyl radical; or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents -Z₃ and Z₃ represents Z_(3c), Z_(3d) or Z_(3e);    -   Z_(3d) represents a (C₃-C₇)cycloalkyl or heterocycloalkyl        radical;        and more particularly    -   Z_(3c) represents a heteroaryl radical chosen from thienyl,        furyl, indolyl, dihydroindolyl, pyridyl, benzothienyl and        benzofuryl; or an aryl radical chosen from phenyl, naphthyl and        fluorenyl;    -   the heteroaryl radical being optionally substituted by one or        more identical or different substituents chosen from:        (C₁-C₆)alkyl-carbonyl and (C₁-C₆)alkoxy-carbonyl;    -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from: halo, cyano,        nitro, azido, (C₁-C₆)alkoxy-carbonyl-(C₁-C₆)alkenyl, oxy,        —SO₂—NR₃₁R₃₂, heterocycloalkyl, heteroaryl, or        —(CH₂)_(p′)—V₃—Y₃;    -   R₃₁ and R₃₂ form together with the nitrogen atom to which they        are attached, the piperidine ring;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂—, —SO₂NH—,        —NR₁₃—, —NR′₃—C(O)—, —C(O)—NR₁₃—, —NH—C(O)—NR₁₃— or a covalent        bond;    -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals; phenyl; or benzyl;    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;    -   Z_(3d) represents the cyclopropyl, cyclohexyl or piperidinyl        radical, each being able to be substituted by a        (C₁-C₆)alkoxy-carbonyl radical; or a pharmaceutically acceptable        salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents -Z₃ and Z₃ represents Z_(3c), Z_(3d) or Z_(3e);    -   Z_(3d) represents a (C₃-C₇)cycloalkyl or heterocycloalkyl        radical; and more particularly    -   Z_(3c) represents a heteroaryl radical chosen from thienyl,        indolyl and benzothienyl; or an aryl radical chosen from phenyl        and naphthyl;    -   the heteroaryl radical being optionally substituted by one or        more oxy radicals;    -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from: halo, nitro,        heteroaryl or —(CH₂)_(p)—V₃—Y₃;        -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂—, —SO₂NH—,            —NR₁₃—C(O)—, —C(O)—NR₁₃—, —NH—C(O)—NR₁₃— or a covalent bond;        -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical            optionally substituted by one or more identical or different            halo radicals; a phenyl radical; or a benzyl radical;        -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or            (C₁-C₆)alkoxy radical;    -   Z_(3d) represents the cyclopropyl or piperidinyl radical, each        optionally substituted by (C₁-C₆)alkoxy-carbonyl;        and preferably    -   Z₃ represents Z_(3c) or Z_(3e);    -   Z_(3c) represents a phenyl being optionally substituted by one        or more identical or different substituents chosen from nitro        and —(CH₂)_(p′)—V₃—Y₃;        -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂—, —SO₂NH—,            —NR₁₃—C(O)—, —C(O)—NR₁₃— or a covalent bond;        -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical; a            phenyl radical; or a benzyl radical;        -   R′₃ represents the hydrogen atom;    -   Z_(3e) represents

or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, R₃ represents —C(R_(Z3))(R′_(Z3))-Z₃ and Z₃ represents Z_(3b),Z_(3c), Z_(3d) or Z_(3e); or a pharmaceutically acceptable salt thereof.

Very preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))-Z₃ and Z₃ represents Z_(3b) or        Z_(3c);    -   R_(Z3) and R′_(Z3) represent the hydrogen atom;        and more particularly    -   Z_(3b) represents a (C₁-C₆)alkoxy radical;    -   Z_(3c) represents a heteroaryl radical chosen from thienyl,        furyl, pyridyl, benzothienyl and dihydrobenzofuryl; or an aryl        radical chosen from phenyl and naphthyl,    -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from: halo or        —(CH₂)_(p)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂—, —SO₂NH—,        —NR₁₃—C(O)—, —C(O)—NR₁₃—,    -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom;        or a pharmaceutically acceptable salt thereof.

Very preferably, the invention relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))-Z₃ and Z₃ represents Z_(3b) or        Z_(3c);    -   R_(Z3) and R′_(Z3) represent the hydrogen atom;        and more particularly    -   Z_(3b) represents a (C₁-C₆)alkoxy radical    -   Z_(3c) represents a heteroaryl radical chosen from thienyl,        furyl, dihydrobenzofuryl; or a phenyl radical;    -   the phenyl radical being optionally substituted by one or more        identical or different substituents chosen from: nitro or        —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂—, —SO₂NH—,        —C(O)—NR₁₃—,    -   Y₃ represents the hydrogen atom; or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom;        and preferably    -   Z₃ represents Z_(3c);    -   Z_(3c) represents a furyl or phenyl radical, the phenyl radical        being optionally substituted by one or more identical or        different substituents of formula —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂—, —SO₂NH—,        —C(O)—NR₁₃—,    -   Y₃ represents the hydrogen atom; or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom;        or a pharmaceutically acceptable salt thereof.

Very preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))-Z₃ and Z₃ represents Z_(3d) or        Z_(3e);    -   R_(Z3) and R′_(Z3) represent the hydrogen atom or (C₁-C₆)alkyl;    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl, (C₃-C₇)cycloalkyl or        heterocycloalkyl radical;    -   Z_(3e) represents

and more particularly

-   -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl, cyclohexyl or a        tetrahydrofuranyl radical; or a pharmaceutically acceptable salt        thereof.

Very preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))-Z₃ and Z₃ represents Z_(3d) or        Z_(3e);    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl radical;    -   Z_(3e) represents

and preferably Z₃ represents Z_(3e)

or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, R₃ represents —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ and Z₃ representsZ_(3b), Z_(3c) or Z_(3d); or a pharmaceutically acceptable salt thereof.

Very preferably, the invention relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

R₃ represents —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ and Z₃ represents Z_(3b);

and more particularly

-   -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z_(3b) represents a (C₁-C₆)alkoxy, (C₁-C₆)alkylthio or        di((C₁-C₆)alkyl)amino radical; or a pharmaceutically acceptable        salt thereof.

Very preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ and Z₃ represents        Z_(3b);        and more particularly    -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z_(3b) represents a (C₁-C₆)alkoxy or (C₁-C₆)alkylthio radical;        or a pharmaceutically acceptable salt thereof.

Very preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ and Z₃ represents        Z_(3c) or Z_(3d);        and more particularly    -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z_(3c) represents an indolyl or phenyl radical;        -   the phenyl radical being optionally substituted by one or            more identical or different substituents chosen from: halo            and —(CH₂)_(p′)—V₃—Y₃;        -   V₃ represents —SO₂NH—,        -   Y₃ represents the hydrogen atom; or a (C₁-C₆)alkyl radical;    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkyl-amino-carbonyl, (C₁-C₆)alkyl-C(O)—NH—, or        heterocycloalkyl radical optionally substituted by oxy, and        preferably piperidinyl, morpholinyl, pyrrolidine or        imidazolidinyl; or a pharmaceutically acceptable salt thereof.

Very preferably, the invention also relates to compounds of formula I asdefined above, characterized in that X represents —CH—, A represents—C(O)—, and

-   -   R₃ represents —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ and Z₃ represents        Z_(3c) or Z_(3d);        and more particularly    -   Z₃ represents Z_(3d);    -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkylamino-carbonyl, (C₁-C₆)alkyl-C(O)—NH— or        heterocycloalkyl radical, and preferably pyrrolidine or        imidazolidine, optionally substituted by oxy; or a        pharmaceutically acceptable salt thereof.

In the present Application, the symbol −>* corresponds to the attachmentpoint of the radical. When the attachment site is not specified on theradical, this means that the attachment is carried out on one of thesites available on this radical for such an attachment.

Following the definitions of the variable groups A, X, R₁, R₂, R₃ andR₄, the compounds according to the invention can be prepared in liquidphase according to the different procedures A to G described below.

A. Preparation According to Reaction Diagram A:

The compounds of formula (I) according to the invention in which Arepresents —C(O)—, can be prepared according to the following diagram A:

As described in diagram A, the methylated derivative (1) (for X═Ccommercial compound; for X═N compound prepared according to theprocedure of Baumgarten et al, J. Am. Chem. Soc, 1952, 74, 3828-3831,from 6-methyl-3-nitro-pyridin2-amine) can be oxidized to carboxylic acid(2) by an aqueous solution of potassium permanganate at a temperature of100° C. for 3 to 6 hours (according to procedure of Schmelkes et al., J.Am. Chem. Soc, 1944, 1631), or by an aqueous solution of sodiumdichromate in the presence of sulphuric acid at a temperature of 20-90°C. for 1 to 3 hours (according to procedure of Howes et al., European J.Med. Chem., 1999, 34, 225-234). The carboxylic acid (2) can be coupledwith a primary or secondary amine in the presence of a coupling agentsuch as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC),1,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) orcarbonyldiimidazole (CDI) with or without 1-hydroxybenzotriazole (HOBt)in an inert organic solvent such as methylene chloride, tetrahydrofuranor dimethylformamide at ambient temperature for 3 to 24 hours in orderto produce the corresponding amide (3). Treatment of the fluorinated orchlorinated derivative (3) by a primary amine in the presence of aninorganic base such as caesium or potassium carbonate in an inertorganic solvent such as dimethylformamide or acetonitrile at atemperature of 20-100° C. for 2 to 48 hours leads to derivative (4). Thenitro function of compound (4) is reduced by treatment with dihydratetin chloride in an inert solvent such as ethyl acetate ordimethylformamide at a temperature of 60-80° C. for 3 to 15 hours, or bycatalytic hydrogenation in the presence of 10% palladium on carbon in aninert solvent such as methanol, ethanol, ethyl acetate or a mixture ofthese solvents, at a temperature of 18-25° C., for 2 to 8 hours in orderto produce the dianiline (5). The derivative (5) is then treated with anisothiocyanate in the presence of a coupling agent supported or notsupported on a resin such as diisopropylcarbodiimide ordicyclohexylcarbodiimide or N-methylcyclohexylcarbodiimide N-methylpolystyrene resin in an inert solvent such as tetrahydrofuran, methylenechloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hoursin order to produce derivative (6). Alternatively, the derivative (5)can be treated with an isothiocyanate in an inert solvent such astetrahydrofuran, methylene chloride, chloroform or ethanol at atemperature of 20-80° C. for 1-16 hours then the resultant thiourea canbe treated by methyl iodide or yellow mercury (II) oxide in the presenceof a catalytic quantity of sulphur in a polar solvent such as methanolor ethanol for 2 to 24 hours at a temperature of 20-80° C. in order toproduce (6). Compound (6) can be isolated either by flash chromatographyon silica gel, or by addition to the reaction mixture of a nucleophilicreagent supported on a polymer such as for example anaminomethylpolystyrene resin and/or an electrophilic reagent supportedon a polymer such as for example methylisothiocyanate-polystyrene resin,followed by filtration and evaporation of the filtrate.

EXAMPLE A1 methyl4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-2-yl)amino]benzoatedihydrochloride

Stage 1: 3-fluoro-4-nitrobenzoic acid

A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassiumpermanganate (25.5 g, 2.5 eq) in water (1 L) is heated under reflux for6 hours then cooled down to ambient temperature. The mixture is filteredon celite and the aqueous phase is washed twice with diethyl ether(2×300 ml). The aqueous phase is acidified, at 0° C., with a solution ofconcentrated hydrochloric acid then concentrated under reduced pressureat 40° C. to a volume of approximately 300 ml. The precipitate formed isfiltered then washed with petroleum ether and dried in order to producethe expected compound in the form of a white solid (6.9 g; 58% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).

Stage 2: 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (4.4g, 1.1 eq) in solution in chloroform (25 ml) and 1-hydroxybenzotriazole(HOBt) (3.05 g, 1.1 eq) in solution in THF (40 ml) are addedsuccessively to 3-fluoro-4-nitrobenzoic acid (3.8 g, 1 eq) in solutionin anhydrous THF (30 ml). The mixture is stirred for 1 hour at atemperature of approximately 20° C. then diisoamylamine (3.6 g, 1.1 eq)in solution in THF (30 ml) is added. After stirring for 16 hours at atemperature of approximately 20° C., the reaction mixture isconcentrated under reduced pressure at 40° C. The residue is taken up indichloromethane (200 ml) and water (70 ml). After decantation andextractions, the combined organic phases are washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C.Purification of the compound by flash chromatography on silica gel(eluent: heptane/ethyl acetate 9:1) produces the expected compound inthe form of a yellow oil (4.3 g; 65% yield).

MS/LC: calculated MM=324.4; m/z=325.2 (MH+)

NMR (¹H, 400 Mhz, DMSO-d₆): δ 0.69 (m, 6H), 0.93 (m, 6H), 1.35-1.60 (m,6H), 3.09 (m, 2H), 3.41 (m, 2H), 7.38 (d, 1H), 7.63 (d, 1H), 8.21 (t,1H).

Stage 3: tert-butyl3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitrophenyl)amino]propylcarbamate

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (1.6 g, 1eq), N-Boc-1,3-diaminopropane (0.9 g, 1.2 eq) and potassium carbonate(1.35 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5hours then concentrated under reduced pressure at 40° C. The residue istaken up in dichloromethane (100 ml) and water (40 ml). Afterdecantation and extractions, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then concentrated under reduced pressureat 40° C. Purification of the residue by flash chromatography on silicagel (eluent: heptane/ethyl acetate 8:2 to 6:4) produces the expectedcompound in the form of a yellow oil (2.2 g; 96% yield).

MS/LC: calculated MM=478.6; m/z=479.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68 (m, 6H), 0.92 (m, 6H), 1.36 (s, 9H),1.31-1.69 (m, 8H), 3.0 (m, 2H), 3.09 (m, 2H), 3.38 (m, 4H), 6.53 (d,1H), 6.88 (m, 2H), 8.10 (d, 1H), 8.26 (m, 1H).

Stage 4: tert-butyl3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate

Tert-butyl3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitrophenyl)amino]propylcarbamate(1.65 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (130 ml),and 10% palladium on carbon (165 mg) are introduced into an autoclave.After stirring for 3 hours under a hydrogen atmosphere (3 bar) at atemperature of approximately 20° C., the catalyst is eliminated byfiltration on celite and the filtrate is concentrated under reducedpressure at 40° C. in order to produce the expected compound in the formof an oil (1.35 g; 89% yield).

MS/LC: calculated MM=448.6; m/z=449.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.81 (m, 12H), 1.37 (s, 9H), 1.32-1.53 (m,6H), 1.70 (m, 2H), 3.0 (m, 4H), 3.26 (m, 4H), 4.47 (m, 1H), 4.79 (s,2H), 6.35-6.51 (m, 3H), 6.85 (m, 1H).

Stage 5: methyl4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate

4-methoxycarbonylphenyl isothiocyanate (327 mg, 1.5 eq) andN-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are added successively toa solution oftert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate(500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated underreflux for 17 hours then cooled down to ambient temperature andaminomethylpolystyrene resin (acquired from Novabiochem, 2 eq) is added.After stirring for 4 hours at ambient temperature, the mixture isfiltered on frit and the filtrate is concentrated under reduced pressureat 40° C. Purification of the residue by flash chromatography on silicagel (eluent: heptane/ethyl acetate 1:1) produces the expected compoundin the form of a white solid (409 mg; 60% yield).

MS/LC: calculated MM=607.8; m/z=608.1 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.65-0.90 (m, 12H), 1.36 (s, 9H),1.31-1.44 (m, 6H), 1.81 (m, 2H), 3.0 (m, 2H), 3.26-3.39 (m, 4H), 3.82(s, 3H), 4.29 (m, 2H), 6.95 (m, 1H), 7.04 (d, 1H), 7.36 (s, 1H), 7.44(d, 1H), 7.94 (AB, 2H), 8.02 (AB, 2H), 9.34 (s, 1H).

Stage 6: methyl4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-2-yl)amino]benzoatedihydrochloride

A solution of hydrochloric acid in dioxane (4N, 2 ml) is added to asolution of methyl4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate(180 mg) in ethyl acetate (2 ml). After stirring for 1 hour at atemperature of approximately 20° C., the mixture is concentrated underreduced pressure at 40° C. The solid obtained is washed with ethyl etherand dried (165 mg; 96% yield).

MS/LC: calculated MM=507.7; m/z=508.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.63-0.98 (m, 12H), 1.45 (m, 6H), 2.08 (m,2H), 2.98 (m, 2H), 3.12-3.45 (m, 4H), 3.85 (s, 3H), 4.59 (m, 2H), 7.20(d, 1H), 7.46 (d, 1H), 7.67 (s, 1H), 7.90 (m, 2H), 8.01-8.07 (m, 5H),11.08 (m, 1H).

EXAMPLE A22-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamidedihydrochloride

Stage 1:N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-ylpropyl)amino]benzamide

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (430 mg, 1eq, prepared according to Example A1), 3-piperidino-propylamine (212 mg,1.1 eq) and potassium carbonate (365 mg, 2 eq) in acetonitrile (10 ml)is heated under reflux for 3 hours then concentrated under reducedpressure at 40° C. The residue is taken up in dichloromethane (50 ml)and water (20 ml). After decantation and extractions, the combinedorganic phases are washed with salt water, dried over Na₂SO₄ thenconcentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: ethyl acetate100%) produces the expected compound in the form of a yellow oil (460mg; 78% yield).

MS/LC: calculated MM=446.6; m/z=447.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68 (d, 6H), 0.92 (d, 6H), 1.31-1.69 (m,12H), 1.74 (m, 2H), 2.32 (m, 6H), 3.10 (m, 2H), 3.38 (m, 4H), 6.53 (d,1H), 6.91 (m, 1H), 8.09 (d, 1H), 8.44 (t, 1H).

Stage 2:2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamidedihydrochloride

N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-yl-propyl)amino]benzamide(44 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (1.5 ml),and 10% palladium on carbon (5 mg) are introduced into a haemolysis tubeplaced in an autoclave. After stirring for 3 hours under a hydrogenatmosphere (3 bar) at a temperature of approximately 20° C., thecatalyst is eliminated by filtration on celite and the filtrate isconcentrated under reduced pressure at 40° C. 4-acetylphenylisothiocyanate (27 mg, 1.5 eq) andN-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; charge 1.9 mmol/g; 158 mg, 3 eq) are added successively tothe aniline thus obtained, in solution in tetrahydrofuran (2 ml). Themixture is heated under reflux for 18 hours then cooled down to ambienttemperature and aminomethylpolystyrene resin (acquired from Novabiochem,2 eq) is added. After stirring for 4 hours at ambient temperature, themixture is filtered on frit and the filtrate is concentrated underreduced pressure at 40° C. Purification of the residue by flashchromatography on silica gel (eluent: 100% dichloromethane todichloromethane/methanol 9:1) produces the expected compound in the formof a base. The corresponding hydrochloride salt is formed by adding a 1Nsolution of hydrochloric acid in ether. The precipitate obtained isfiltered and dried in order to produce the expected dihydrochloridecompound.

MS/LC: calculated MM=559.8; m/z=560.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68 (m, 6H), 0.94 (m, 6H), 1.31-1.56 (m,6H), 1.57-1.90 (m, 6H), 2.28 (m, 2H), 2.60 (s, 3H), 2.86 (m, 2H), 3.21(m, 4H), 3.40 (m, 4H), 4.62 (t, 2H), 7.24 (AB, 1H), 7.47 (AB, 1H), 7.76(s, 1H), 7.81 (m, 2H), 8.07 (m, 2H), 10.40 (s, 1H), 11.64 (m, 1H).

EXAMPLE A32-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride

Stage 1:3-{[3-(dimethylamino)propyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.5 g, 1eq, prepared according to Example A1), 3-diethylamino-propylamine (877mg, 1.1 eq) and potassium carbonate (2.13 g, 2 eq) in acetonitrile (80ml) is heated under reflux for 5 hours then concentrated under reducedpressure at 40° C. The residue is taken up in dichloromethane (130 ml)and water (50 ml). After decantation and extractions, the combinedorganic phases are washed with salt water, dried over Na₂SO₄ thenconcentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent:dichloromethane/methanol 9:1) produces the expected compound in the formof a yellow oil (2.1 g mg; 68% yield).

MS/LC: calculated MM=406.6; m/z=407.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68 (d, 6H), 0.92 (d, 6H), 1.31-1.51 (m,5H), 1.59 (m, 1H), 1.74 (m, 2H), 2.14 (s, 6H), 2.31 (t, 2H), 3.11 (m,2H), 3.39 (m, 4H), 6.53 (d, 1H), 6.90 (s, 1H), 8.09 (d, 1H), 8.57 (t,1H).

Stage 2:2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydro chloride

3-{[3-(dimethylamino)propyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide(81 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (4 ml),and 10% palladium on carbon (8 mg) are introduced into a haemolysis tubeplaced in an autoclave. After stirring for 3 hours under a hydrogenatmosphere (3 bar) at a temperature of approximately 20° C., thecatalyst is eliminated by filtration on celite and the filtrate isconcentrated under reduced pressure at 40° C. Cyclohexyl isothiocyanate(58 mg, 2 eq) is successively added to the aniline thus obtained, insolution in tetrahydrofuran (2 ml). The mixture is heated under refluxfor 3 hours then cooled down to ambient temperature and concentratedunder reduced pressure. Yellow mercury (II) oxide (87 mg, 2 eq) andsulphur (1.4 mg) are successively added to the thiourea thus formed insolution in ethanol (3 ml). The mixture is heated for 17 hours underreflux then cooled down to ambient temperature and filtered onmicrofibre paper. The filtrate is concentrated under reduced pressure.Purification of the residue by flash chromatography on silica gel(eluent: 100% dichloromethane to dichloromethane/methanol 9:1) producesthe expected compound in the form of a base. The correspondinghydrochloride salt is formed by adding a 1N solution of hydrochloricacid in ether. The precipitate obtained is filtered and dried in orderto produce the expected dihydrochloride compound (87 mg, 78% yield).

MS/LC: calculated MM=483.7; m/z=484.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.58-1.03 (m, 12H), 1.18 (m, 1H),1.30-1.71 (m, 11H), 1.80 (m, 2H), 2.01 (m, 4H), 2.73 (s, 6H), 3.14 (m,4H), 3.25 (m, 2H), 3.71 (m, 1H), 4.32 (m, 2H), 7.16 (m, 1H), 7.39 (m,1H), 7.54 (m, 1H), 8.42 (m, 1H), 10.40 (m, 1H), 13.41 (m, 1H).

Preparation of Non-Commercial Isothiocyanates:

A primary amine can be converted to isothiocyanate, by treatment withthiophosgene in the presence of a tertiary base such as triethylamine,in an aprotic solvent such as dichloromethane or tetrahydrofuran, at atemperature of 0-20° C. for 0.3 to 2 hours, or alternatively bytreatment with carbon disulphide and cyclohexylcarbodiimide supported ornot supported on a resin in an aprotic solvent such as dichloromethaneor tetrahydrofuran, at a temperature of 0-70° C. for 0.3 to 15 hours.

N-(4-isothiocyanatophenyl)acetamide

Thiophosgene (0.56 ml, 1.1 eq) is added dropwise to a solution cooleddown to 0° C., of N-(4-aminophenyl)acetamide (1 g, 1 eq) andtriethylamine (2.8 ml, 3 eq) in tetrahydrofuran (130 ml). The mixture isstirred for 30 minutes at 0° C. then the cold bath is removed and thestirring is continued for another 30 minutes. Water (70 ml) and diethylether (150 ml) are added to the mixture. After decantation andextractions, the organic phases are combined, washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C. Thesolid obtained is recrystallized from a dichloromethane/petroleum ethermixture (0.95 g; 75% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 2.04 (s, 3H), 7.35 (AB, 2H), 7.63 (AB,2H), 10.14 (s, 1H).

The following isothiocyanates were prepared according to the sameprocedure as that described for N-(4-isothiocyanatophenyl)acetamide:

Preparation of N-(4-isothiocyanatophenyl)-N′-methoxyurea

Carbonyl-di-imidazole (1.62 g, 2 eq) is added to a solution cooled downto 0° C., of tert-butyl 4-aminophenylcarbamate (1.04 g) in anhydrousdichloromethane (100 ml). The mixture is taken to a temperature of 20°C. and is stirred at this temperature for 15 hours. Triethylamine (7 ml,10 eq) followed by O-methylhydroxylamine hydrochloride (4.2 g, 10 eq)are successively added to the reaction medium cooled down to 0° C. Afterstirring for 3 hours at a temperature of approximately 20° C., watersaturated with sodium hydrogen carbonate and chloroform is added to themixture. After decantation and extractions, the combined organic phasesare washed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. in order to produce tert-butyl4-{[(methoxyamino)carbonyl]amino}phenylcarbamate (1.33 g). A current ofgaseous hydrochloric acid is passed through a suspension of thisderivative in ethyl acetate until the reaction is complete. Theprecipitate obtained is filtered then washed with diethyl ether anddried in order to produce N-(4-aminophenyl)-N′-methoxyurea hydrochloride(1 g).

Thiophosgene (0.38 ml, 1.1 eq) is added dropwise to a solution cooleddown to 0° C., of N-(4-aminophenyl)-N′-methoxyurea hydrochloride (1 g)and triethylamine (3.2 ml, 5 eq) in tetrahydrofuran (90 ml). The mixtureis stirred for 15 min at 0° C. then water and diethyl ether are added.After decantation and extractions, the phases organic are combined,washed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. Purification by flash chromatography onsilica gel (eluent: heptane/ethyl acetate 7:3 to 3:7) produces theexpected compound (630 mg; 62% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 3.61 (s, 3H), 7.34 (AB, 2H), 7.67 (AB,2H), 9.11 (s, 1H), 9.65 (s, 1H).

Preparation of Non-Commercial Acyl-Isothiocyanates:

Acyl-isothiocyanates can be prepared starting from the correspondingacid chlorides by treatment with potassium thiocyanate in an aproticsolvent such as acetonitrile at a temperature of 0-60° C. for 0.2-5hours.

Methyl 4-isothiocyanatocarbonylbenzoate

Potassium thiocyanate (1.08 g) is added to a solution of methyl4-chlorocarbonylbenzoate (2 g) in acetonitrile (30 ml). After stirringfor 1 hour at approximately 20° C., the mixture is filtered and thefiltrate is concentrated under reduced pressure at 40° C. The solidobtained is purified by flash chromatography on silica gel (eluent:heptane/ethyl acetate 1:1) in order to produce the expected compound(2.1 g; 95% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 3.88 (s, 3H), 8.0 (m, 4H).

The following isothiocyanates were prepared according to the sameprocedure as that described for the methyl4-isothiocyanatocarbonylbenzoate:

According to reaction diagram A and in a fashion analogous to theprocedure described for the synthesis of methyl4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-2-yl)amino]benzoate dihydrochloride,2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamidedihydrochloride or2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride, the following compounds were prepared:

in which R₁R₂N represents one of the radicals below:

and R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

B. Preparation According to Reaction Diagram B:

The compounds of formula (I) according to the invention in which Arepresents —C(O)—, can also be prepared according to the followingdiagram B:

As described in diagram B, the carboxylic acid (2) can be converted tomethyl ester (7) either by treatment with a solution oftrimethylsilyl-diazomethane at a temperature of 0-20° C., or byformation of a carboxylate salt using an inorganic base such as lithiumhydroxide dihydrate or caesium carbonate, at ambient temperature for 30minutes to 2 hours, in an inert organic solvent such as tetrahydrofuran,followed by the addition of dimethylsulphate at ambient temperature andstirring under reflux for 5 to 15 hours. The fluorinated or chlorinatedderivative (7) can be treated with a primary amine in the presence of aninorganic base such as caesium or potassium carbonate in an inertorganic solvent such as dimethylformamide or acetonitrile at atemperature of 20-100° C. for 2 to 48 hours in order to producederivative (8). The nitro function of compound (8) can be reduced bytreatment with tin chloride dihydrate in an inert solvent such as ethylacetate or dimethylformamide, at a temperature of 60-80° C. for 3 to 15hours, or by catalytic hydrogenation in the presence of 10% palladium oncarbon in an inert solvent such as methanol, ethanol, ethyl acetate or amixture of these solvents, at a temperature of 18-25° C., for 2 to 8hours, in order to produce the dianiline (9). The derivative (9) is thentreated with an isothiocyanate in the presence of a coupling agent suchas diisopropylcarbodiimide or dicyclohexylcarbodiimide in an inertsolvent such as tetrahydrofuran, methylene chloride or chloroform at atemperature of 20-70° C. for 2 to 72 hours in order to producederivative (10). Alternatively, derivative (9) can be treated with anisothiocyanate in an inert solvent such as tetrahydrofuran, methylenechloride, chloroform or ethanol at a temperature of 20-80° C. for 1-16hours, then the resultant thiourea can be treated with methyl iodide oryellow mercury (II) oxide in the presence of a catalytic quantity ofsulphur in a polar solvent such as methanol or ethanol for 2 to 24 hoursat a temperature of 20-80° C. in order to produce (10). The methyl ester(10) can then be saponified in the presence of an inorganic base such aslithium hydroxide dihydrate in a mixture of polar solvents such as waterand tetrahydrofuran at a temperature of 20 to 70° C. for 3 to 17 hours.The resultant carboxylic acid (11) can be coupled with a primary orsecondary amine in the presence of a coupling agent such asdiisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) orcarbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole (HOBt)in an inert organic solvent such as methylene chloride, tetrahydrofuranor dimethylformamide at ambient temperature for 3 to 24 hours in orderto produce the corresponding amide (6) which can be isolated, either byflash chromatography on silica gel, or by the addition to the reactionmixture of a nucleophilic reagent supported on a polymer such as forexample an aminomethylpolystyrene resin and an electrophilic reagentsupported on a polymer such as for examplemethylisothiocyanate-polystyrene resin, followed by filtration andevaporation of the filtrate.

EXAMPLE B11-(3-aminopropyl)-6-(piperidin-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-aminedihydrochloride

Stage 1: methyl 3-fluoro-4-nitrobenzoate

A solution of trimethylsilyldiazomethane (2M in hexane, 50 ml, 4 eq) isslowly added to a solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 1 eq)in methanol (70 ml) until the gas evolution ceases. The excesstrimethylsilyldiazomethane is consumed by the dropwise addition ofacetic acid until the solution becomes discoloured. The mixture is thenconcentrated under reduced pressure at a temperature of approximately40° C. Water (200 ml) and dichloromethane (300 ml) are added to theresidue. After decantation and extractions, the combined organic phasesare washed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. The solid obtained is washed with petroleumether and dried (4.4 g; 87% yield).

NMR (¹H, 400 MHz, CDCl₃): δ 4.0 (s, 3H), 7.97 (m, 2H), 8.11 (d, 1H).

Stage 2: methyl3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)-4-nitrobenzoate

A mixture of methyl 3-fluoro-4-nitrobenzoate (5.8 g, 1 eq),N-Boc-1,3-diaminopropane (5.75 g, 1.1 eq) and potassium carbonate (8.04g, 2 eq) in acetonitrile (200 ml) is heated under reflux for 2 hoursthen concentrated under reduced pressure at 40° C. The residue is takenup in dichloromethane (200 ml) and water (100 ml). After decantation andextractions, the combined organic phases are washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C. Thesolid obtained is washed with petroleum ether and dried (10.2 g; 99%yield).

NMR (¹H, 400 MHz, CDCl₃): δ 1.45 (s, 9H), 1.95 (m, 2H), 3.30 (m, 2H),3.44 (m, 2H), 3.95 (s, 3H), 4.67 (m, 1H), 7.25 (m, 1H), 7.55 (s, 1H),8.04 (m, 1H), 8.22 (m, 1H).

Stage 3: methyl4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)benzoate

Methyl 3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)-4-nitrobenzoate(10.2 g) in solution in a mixture of ethyl acetate/methanol 3:1 (300ml), and 10% palladium on carbon (1.02 g) are introduced into anautoclave. After stirring for 4 hours under a hydrogen atmosphere (3bar) at a temperature of approximately 20° C., the catalyst iseliminated by filtration on celite and the filtrate is concentratedunder reduced pressure at 40° C. in order to produce the expectedcompound in the form of an oil (7.75 g; 83% yield).

MS/LC: calculated MM=323.4; m/z=324.2 (MH+)

NMR (¹H, 400 MHz, CDCl₃): 1.45 (s, 9H), 1.85 (m, 2H), 3.24 (m, 2H), 3.30(m, 2H), 3.86 (m, 5H), 4.68 (m, 1H), 6.68 (d, 1H), 7.34 (s, 1H), 7.45(d, 1H).

Stage 4: methyl1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylate

3,4,5-trimethoxyphenyl isothiocyanate (6.6 g, 1.2 eq) anddiisopropylcarbodiimide (9.1 g, 3 eq) are successively added to asolution of methyl4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino) benzoate (7.75g, 1 eq) in tetrahydrofuran (130 ml). The mixture is heated under refluxfor 16 hours then cooled down to ambient temperature and concentratedunder reduced pressure at 40° C. Water (100 ml) and dichloromethane (200ml) are added to the residue obtained. After decantation andextractions, the combined organic phases are washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C.Purification of the residue by flash chromatography on silica gel(eluent: heptane/ethyl acetate 8:2 to 3:7) produces the expectedcompound in the form of a solid which is washed with ether (4.4 g; 36%yield).

MS/LC: calculated MM=514.5; m/z=515.3 (MH+)

NMR (¹H, 400 MHz, CDCl₃): 1.54 (s, 9H), 2.11 (m, 2H), 3.26 (m, 2H), 3.83(m, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 4.22 (m, 2H), 5.03 (m, 1H), 7.23(s, 2H), 7.53 (d, 1H), 7.90 (s, 1H), 7.92 (d, 1H), 9.12 (m, 1H).

Stage 5:1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylicacid

Lithium hydroxide (2.18 g, 6 eq) is added to a solution of methyl1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylate(4.4 g, 1 eq) in a mixture of tetrahydrofuran (40 ml) and water (30 ml).The mixture is heated under reflux for 18 hours then cooled down toambient temperature and concentrated under reduced pressure at 40° C.Dichloromethane (150 ml) and water (100 ml) are added to the residue.The mixture is acidified by the addition of acetic acid to pH 5. Afterdecantation and extractions, the combined organic phases are dried oversodium sulphate and concentrated under reduced pressure. The solidobtained is washed with ethyl ether (3.95 g; 93%).

MS/LC: calculated MM=500.5; m/z=501.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): 1.37 (s, 9H), 1.83 (m, 2H), 3.03 (m, 2H),3.61 (s, 3H), 3.80 (s, 6H), 4.27 (m, 2H), 7.0 (m, 1H), 7.31 (s, 2H),7.35 (d, 1H), 7.71 (d, 1H), 7.87 (s, 1H), 8.97 (s, 1H).

Stage 6:1-(3-aminopropyl)-6-(piperidin-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-aminedihydrochloride

A solution of carbonyldiimidazole (CDI) (18 mg, 1.1 eq) in chloroform(0.2 ml) is added to a solution of1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylicacid (50 mg, 1 eq) in tetrahydrofuran (0.45 ml) and dimethylformamide(0.05 ml). The mixture is stirred for 16 hours at a temperature ofapproximately 20° C., then a solution of piperidine (17 mg, 2 eq) intetrahydrofuran (0.2 ml) is added. After stirring for 18 hours at atemperature of approximately 20° C., the mixture is diluted withdichloromethane (3 ml), and aminomethylpolystyrene resin (2 eq),TBD-methyl-polystyrene resin (2 eq) and methylisothiocyanate-polystyreneresin (4 eq) are added. After stirring for 6 hours at approximately 20°C., the mixture is filtered and the filtrate is concentrated underreduced pressure at 40° C. The residue obtained is dissolved in ethylacetate (0.5 ml) and a solution of hydrochloric acid (1N in diethylether, 3 ml) is added. After stirring for 1 hour at a temperature ofapproximately 20° C., the precipitate obtained is filtered and dried inorder to produce the expected compound (35 mg, 65%).

MS/LC: calculated MM=467.56; m/z=467.9 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): 1.48-1.63 (m, 6H), 2.05 (m, 2H), 2.90 (m,2H), 3.50 (m, 4H), 3.65 (s, 3H), 3.79 (s, 6H), 4.45 (m, 2H), 7.10-7.60(m, 5H), 7.54 (m, 1H), 7.94 (m, 3H), 8.41 (m, 1H), 14.3 (m, 1H).

According to reaction diagram B and in a fashion analogous to theprocedure described for the synthesis of1-(3-aminopropyl)-6-(piperidin-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-aminedihydrochloride, the following compounds were prepared:

in which R₁R₂N represents one of the radicals below:

R₃ represents the radical below:

and R₄ represents one of the radicals below:

C. Preparation According to Reaction Diagram C:

As described in diagram C, the derivative (12), prepared according toreaction diagrams A or B can be treated with an organic or inorganicacid such as trifluoroacetic acid or hydrochloric acid (aqueous or ingaseous form) in an aprotic solvent such as dichloromethane, diethylether or ethyl acetate at a temperature of 0-20° C. for 0.5 to 5 hours,in order to produce the amine (13). The amine (13) can react with analdehyde in a protic or aprotic solvent, such as dichloromethane,tetrahydrofuran or methanol, for 1 to 15 hours at a temperature of 0-50°C. The resultant imine is then reduced in situ by a reducing agentsupported or not supported on a resin, preferably sodiumtriacetoxyborohydride, sodium cyanoborohydride or borohydride supportedon a resin, with or without the presence of an acid such as acetic acid,at a temperature of 20 to 50° C. for a duration of 0.2 to 5 hours, inorder to produce compound (14). The secondary amine (14) can optionallyundergo a second reducing amination under the same operating conditionsas those described previously in order to produce the tertiary amine(14′).

EXAMPLE C1N,N-diisobutyl-1-[3-(neopentylamino)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamidedihydrochloride

Stage1:1-(3-aminopropyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide

A current of dry HCl is passed through a solution of tert-butyl3-{6-[(diisobutylamino)carbonyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate(350 mg; prepared according to diagram A) in ethyl acetate (30 ml),cooled down to 0° C., until TLC (eluent: 100% ethyl acetate) shows thetotal disappearance of the starting product. The mixture is thenconcentrated under reduced pressure at 40° C. The solid obtained istriturated in ethyl ether then filtered, washed with dichloromethane anddried. The dihydrochloride obtained is taken up in dichloromethane andwater saturated with sodium hydrogen carbonate. After decantation andextractions, the combined organic phases are washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C. inorder to produce the expected compound in the form of the free base (275mg; 94% yield).

MS/LC: calculated MM=511.6; m/z=512.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.82 (m, 12H), 1.87 (m, 4H), 2.58 (m, 2H),3.21 (m, 4H), 3.62 (s, 3H), 3.78 (s, 6H), 4.25 (t, 2H), 7.0 (AB, 1H),7.20 (s, 2H), 7.26 (s, 1H), 7.34 (AB, 1H).

Stage 2:N,N-diisobutyl-1-[3-(neopentylamino)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamidedihydrochloride

A solution of1-(3-aminopropyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide(100 mg, 1 eq) and trimethylacetaldehyde (25 mg, 1.5 eq) indichloromethane (1 ml) is stirred for 4 hours at a temperature ofapproximately 20° C. The mixture is diluted with methanol (1 ml) thensodium triacetoxyborohydride is added (41 mg, 2 eq). After 1 hour at atemperature of approximately 20° C., dichloromethane (20 ml) and watersaturated with sodium hydrogen carbonate (10 ml) are added to themixture. After decantation and extractions, the combined organic phasesare washed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. Purification of the residue by flashchromatography on silica gel (eluent: 100% dichloromethane todichloromethane/methanol 9:1) produces the expected compound in the formof a base. The corresponding hydrochloride salt is formed by adding a 1Nsolution of hydrochloric acid in ether. The precipitate obtained isfiltered and dried in order to produce the expected dihydrochloridecompound (83 mg, 65% yield).

MS/LC: calculated MM=581.8; m/z=582.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.67 (m, 6H), 0.95 (m, 6H), 0.99 (s, 9H),1.82 (m, 1H), 2.06 (m, 1H), 2.27 (m, 2H), 2.71 (m, 2H), 3.10 (m, 4H),3.28 (m, 2H), 3.70 (s, 3H), 3.81 (s, 6H), 4.58 (t, 2H), 6.99 (m, 2H),7.22 (AB, 1H), 7.41 (AB, 1H), 7.69 (s, 1H), 8.72 (m, 2H), 11.42 (m, 1H),13.02 (m, 1H).

Preparation According to Reaction Diagram C′:

The compounds (14) for which s=3 can also be prepared according to thefollowing diagram C′:

As described in diagram C′, the derivative (15) prepared according toreaction diagram A can be treated either with an organic acid such aspyridinium tosylate or paratoluenesulphonic acid in an aprotic solventsuch as acetone in the presence of water, at a temperature of 20-70° C.for 2 to 12 hours, or by an inorganic acid such as aqueous hydrogenchloride in an aprotic solvent such as tetrahydrofuran at a temperatureof 0-20° C. for 6 to 18 hours in order to produce compound (16). Thealdehyde (16) can then be treated with an amine in a protic or aproticsolvent such as dichloromethane, tetrahydrofuran or methanol for 1 to 18hours at a temperature of 20° C. The resultant imine is then reduced insitu by a reducing agent, preferably sodium triacetoxyborohydride orsodium cyanoborohydride, in the presence or absence of an acid such asacetic acid, at a temperature of 20-50° C. for a duration of 0.2 to 6hours, in order to produce compound (17). The secondary amine (17) canoptionally undergo a second reducing amination under the same operatingconditions as those described previously in order to produce thetertiary amine (17′).

EXAMPLE C1′ 2-[(4-acetylphenyl)amino]-1-{3-[cyclohexylmethylamino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride

Stage 1:3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide preparedaccording to Example A1 (1.86 g, 1 eq), 2-(2-aminoethyl)-1,3-dioxolane(0.8 g, 1.2 eq) and potassium carbonate (1.58 g, 2 eq) in acetonitrile(150 ml) is heated under reflux for 3 hours then concentrated underreduced pressure at 40° C. The residue is taken up in dichloromethane(150 ml) and water (60 ml). After decantation and extractions, thecombined organic phases are washed with salt water, dried over Na₂SO₄then concentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: heptane/ethylacetate 8:2 to 7:3) produces the expected compound in the form of anorange-yellow oil (2.4 g; 98% yield).

MS/LC: calculated MM=421.5; m/z=422.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68 (d, 6H), 0.92 (d, 6H), 1.31-1.50 (m,5H), 1.61 (m, 1H), 1.97 (m, 2H), 3.10 (m, 2H), 3.37-3.48 (m, 4H), 3.80(m, 2H), 3.91 (m, 2H), 4.94 (t, 1H), 6.55 (d, 1H), 6.89 (s, 1H), 8.10(d, 1H), 8.39 (t, 1H).

Stage 2:4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide

3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide(2.4 g) in solution in a mixture of ethyl acetate/methanol 2:1 (100 ml),and 10% palladium on carbon (240 mg) are introduced into an autoclave.After stirring for 4 hours under a hydrogen atmosphere (3 bar) at atemperature of approximately 20° C., the catalyst is eliminated byfiltration on celite and the filtrate is concentrated under reducedpressure at 40° C. in order to produce the expected compound in the formof an oil (2.02 g; 89% yield).

MS/LC: calculated MM=391.5; m/z=392.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.80 (m, 12H), 1.40 (m, 6H), 1.90 (m, 2H),3.10 (m, 2H), 3.29 (m, 4H), 3.77 (m, 2H), 3.90 (m, 2H), 4.54 (m, 1H),4.78 (s, 2H), 4.93 (t, 1H), 6.36-6.52 (m, 1H).

Stage 3:2-[(4-acetylphenyl)amino]-1-[2-(1,3-dioxolan-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

4-acetylphenyl isothiocyanate (1.1 g, 1.2 eq) anddiisopropylcarbodiimide (1.95 g, 3 eq) are successively added to asolution of4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide(2 g, 1 eq) in tetrahydrofuran (50 ml). The mixture is heated underreflux for 18 hours then cooled down to ambient temperature andconcentrated under reduced pressure at 40° C. Water (100 ml) anddichloromethane (200 ml) are added to the residue obtained. Afterdecantation and extractions, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then concentrated under reduced pressureat 40° C. Purification of the residue by flash chromatography on silicagel (eluent: heptane/ethyl acetate 4:6) produces the expected compoundin the form of a white foam (1.8 g; 66% yield).

MS/LC: calculated MM=534.7; m/z=535.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.80 (m, 12H), 1.44 (m, 6H), 2.01 (m, 2H),2.52 (s, 3H), 3.30 (t, 4H), 3.72 (t, 2H), 3.85 (m, 2H), 4.39 (t, 2H),4.83 (t, 1H), 7.05 (AB, 1H), 7.30 (s, 1H), 7.44 (AB, 1H), 7.96 (s, 4H),9.37 (s, 1H).

Stage 4:2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-oxopropyl)-1H-benzimidazole-6-carboxamide

A solution of2-[(4-acetylphenyl)amino]-1-[2-(1,3-dioxolan-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide(900 mg) in a mixture of tetrahydrofuran (30 ml) and aqueoushydrochloric acid (3N, 40 ml) is stirred for 18 hours at a temperatureof approximately 20° C. then concentrated under reduced pressure at 40°C. Dichloromethane (100 ml) is added to the remaining aqueous phase.After decantation and extractions, the combined organic phases arewashed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. in order to produce the expected compound inthe form of a beige foam (820 mg, 99% yield).

MS/LC: calculated MM=490.6; m/z=491.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68-0.99 (m, 12H), 1.35 (m, 6H), 2.39 (m,2H), 2.64 (s, 3H), 3.10-3.49 (m, 4H), 3.72 (m, 2H), 4.15 (m, 1H), 4.50(m, 1H), 5.54 (s, 1H), 7.27 (AB, 1H), 7.39 (AB, 1H), 7.64 (s, 1H), 7.82(AB, 1H), 8.15 (AB, 1H).

Stage 5:2-[(4-acetylphenyl)amino]-1-{3-[(cyclohexylmethyl)amino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride

A solution of2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-oxopropyl)-1H-benzimidazole-6-carboxamide(100 mg, 1 eq) and aminomethylcyclohexane (46 mg, 2 eq) is stirred for 4hours at a temperature of approximately 20° C. The mixture is dilutedwith methanol (1 ml), then sodium triacetoxyborohydride (86 mg, 2 eq)and a few drops of acetic acid are added to produce a pH of 5. After 1hour at a temperature of approximately 20° C., dichloromethane (20 ml)and water saturated with sodium hydrogen carbonate (10 ml) are added tothe mixture. After decantation and extractions, the combined organicphases are washed with salt water, dried over Na₂SO₄ then concentratedunder reduced pressure at 40° C. Purification of the residue by flashchromatography on silica gel (eluent: 100% dichloromethane todichloromethane/methanol 9:1) produces the expected compound in the formof a base. The corresponding hydrochloride salt is formed by adding a 1Nsolution of hydrochloric acid in ether. The precipitate obtained isfiltered and dried in order to produce the expected dihydrochloridecompound (83 mg, 62% yield).

MS/LC: calculated MM=587.8; m/z=588.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.68-0.99 (m, 14H), 1.19 (m, 3H),1.29-1.82 (m, 12H), 2.59 (s, 3H), 2.73 (m, 2H), 3.07 (t, 2H), 3.21 (m,2H), 3.43 (m, 2H), 4.64 (t, 2H), 7.24 (AB, 1H), 7.47 (AB, 1H), 7.37 (s,1H), 7.84 (d, 2H), 8.06 (d, 2H), 8.89 (m, 2H), 11.42 (m, 1H).

According to reaction diagram C or C′ and in a fashion analogous to theprocedure described for the synthesis ofN,N-diisobutyl-1-[3-(neopentylamino)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamidedihydrochloride or2-[(4-acetylphenyl)amino]-1-{3-[(cyclohexylmethyl)amino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride, the followingcompounds were prepared:

in which R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

D. Preparation According to the Reaction Diagram D:

As described in diagram D, the derivative (18) prepared according toreaction diagram A, can be saponified in the presence of an inorganicbase such as lithium hydroxide dihydrate in a mixture of polar solventssuch as water and tetrahydrofuran at a temperature of 20 to 70° C. for 3to 17 hours. The resultant carboxylic acid (19) can be coupled with aprimary or secondary amine in the presence of a coupling agent such asdiisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) orcarbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole (HOBt)in an inert organic solvent such as methylene chloride, tetrahydrofuranor dimethylformamide at ambient temperature for 3 to 24 hours in orderto produce compound (20).

EXAMPLE D11-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride

Stage 1:4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoicacid

Lithium hydroxide (141 mg, 5 eq) is added to methyl4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoateprepared according to reaction diagram A, Example A1, (405 mg, 1 eq) ina mixture of tetrahydrofuran (4 ml) and water (3 ml). The mixture isheated under reflux for 18 hours then cooled down to ambient temperatureand concentrated under reduced pressure at 40° C. Dichloromethane (50ml) and water (20 ml) are added to the residue. The mixture is acidifiedby the addition of acetic acid to pH 5. After decantation andextractions, the combined organic phases are dried over sodium sulphateand concentrated under reduced pressure. The solid obtained is taken upin ethyl ether in order to produce the expected compound (309 mg; 79%).

MS/LC: calculated MM=593.8; m/z=594.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): 0.77 (m, 12H), 1.22-1.55 (m, 6H), 1.36 (s,9H), 1.83 (m, 2H), 3.03 (m, 2H), 3.33 (m, 4H), 4.28 (m, 2H), 6.95-7.90(m, 8H), 9.24 (s, 1H).

Stage 2:1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride

A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) (18 mg, 1.1 eq) in chloroform (1 ml) and a solutionof 1-hydroxybenzotriazole (HOBt) (13 mg, 1.1 eq) in tetrahydrofuran (1ml) are successively added to4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoicacid (50 mg, 1 eq) in anhydrous tetrahydrofuran (1 ml). The mixture isstirred for 1 hour at a temperature of approximately 20° C. then themethylamine is added (2M in THF; 0.86 ml, 2 eq). After stirring for 17hours at a temperature of approximately 20° C., the mixture is dilutedwith dichloromethane (3 ml) followed by the addition ofaminomethylpolystyrene resin (2 eq), TBD-methyl polystyrene resin (2 eq)and methylisothiocyanate-polystyrene resin (4 eq). After stirring for 6hours at approximately 20° C., the mixture is filtered and the filtrateis concentrated under reduced pressure at 40° C. The residue obtained isdissolved in dichloromethane (3 ml) and washed with a saturated aqueoussolution of sodium hydrogen carbonate. The organic phase is dried oversodium sulphate and concentrated at a temperature of approximately 40°C. The residue obtained is dissolved in ethyl acetate (0.5 ml) and asolution of hydrochloric acid (4N in dioxane, 2 ml) is added. Afterstirring for 1 hour a temperature of approximately 20° C., theprecipitate obtained is filtered and dried in order to produce theexpected compound (29 mg; 60% yield).

MS/LC: calculated MM=506.7; m/z=507.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): 0.78 (m, 12H), 1.46 (m, 6H), 2.0 (m, 2H),2.77 (d, 3H), 2.89 (m, 2H), 3.33 (m, 4H), 4.45 (m, 2H), 7.07 (d, 1H),7.43 (d, 1H), 7.48 (s, 1H), 7.84 (m, 5H), 7.97 (m, 2H), 8.28 (m, 2H),9.49 (m, 1H).

According to reaction diagram D and in a fashion analogous to theprocedure described for the synthesis of1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamidedihydrochloride, the following compounds were prepared

in which R₃ represents one of the radicals below:

E. Preparation According to Reaction Diagram E:

As described in diagram E, the derivative (21) prepared according toreaction diagram A, can be reduced by treatment with tin chloridedihydrate in an inert solvent such as ethyl acetate ordimethylformamide, at a temperature of 60-80° C. for 3 to 15 hours, orby catalytic hydrogenation in the presence of 10% palladium on carbon inan inert solvent such as methanol, ethanol, ethyl acetate or a mixtureof these solvents, at a temperature of 18-25° C., for 2 to 8 hours, inorder to produce aniline (22). Compound 23 can be treated with anisocyanate in an aprotic solvent such as dichloromethane ortetrahydrofuran at a temperature of 20-60° C. for 2 to 24 hours oralternatively with carbonyldiimidazole (CDI) in an aprotic solvent suchas dichloromethane or tetrahydrofuran at a temperature of 0-60° C. for 6to 24 hours, followed by a primary amine at a temperature of 20-60° C.for 2 to 24 hours, in order to produce the urea (23).

EXAMPLE E11-(3-aminopropyl)-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

Stage 1: tert-butyl3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate

4-nitrophenyl isothiocyanate (305 mg, 1.5 eq) andN-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are successively added toa solution oftert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamateprepared according to Example A1 (500 mg, 1 eq) in tetrahydrofuran (30ml). The mixture is heated under reflux for 18 hours then cooled down toambient temperature and filtered on frit. The filtrate is concentratedunder reduced pressure at 40° C. Purification of the residue by flashchromatography on silica gel (eluent: heptane/ethyl acetate 7:3 to 2:8)produces the expected compound in the form of a yellow solid (584 mg;88% yield).

MS/LC: calculated MM=594.7; m/z=595.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.64-0.95 (m, 12H), 1.36 (s, 9H),1.31-1.65 (m, 6H), 1.82 (m, 2H), 3.0 (m, 2H), 3.15-3.39 (m, 4H), 4.32(t, 2H), 6.95 (m, 1H), 7.05 (d, 1H), 7.40 (s, 1H), 7.48 (d, 1H), 8.11(AB, 2H), 8.26 (AB, 2H), 9.71 (s, 1H).

Stage 2: tert-butyl3-(2-[(4-aminophenyl)amino]-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-1-yl)propylcarbamate

Tert-butyl3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate(580 mg) in solution in a mixture of ethyl acetate/methanol 3:1 (40 ml),and 10% palladium on carbon (58 mg) are introduced into an autoclave.After stirring for 15 hours under a hydrogen atmosphere (3 bar) at atemperature of approximately 20° C., the catalyst is eliminated byfiltration on celite and the filtrate is concentrated under reducedpressure at 40° C. in order to produce the expected compound in the formof a foam (480 mg; 87% yield).

MS/LC: calculated MM=564.7; m/z=565.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.86 (m, 12H), 1.37 (s, 9H), 1.31-1.58 (m,6H), 1.79 (m, 2H), 3.01 (m, 2H), 3.15-3.39 (m, 4H), 4.15 (t, 2H), 4.80(m, 2H), 6.56 (m, 2H), 6.94 (d, 2H), 7.21 (AB, 2H), 7.40 (AB, 2H), 8.45(s, 1H).

Stage 3: tert-butyl3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-1H-benzimidazol-1-yl}propyl carbamate dihydrochloride

A solution of carbonyldiimidazole (CDI) (29 mg, 2 eq) in dichloromethane(2 ml) is added to a solution of tert-butyl3-(2-[(4-aminophenyl)amino]-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-1-yl)propylcarbamate (50mg, 1 eq) in dichloromethane (2 ml). The mixture is stirred for 18 hoursat a temperature of approximately 20° C. then methylamine is added (2Min THF, 0.440 ml, 10 eq). The mixture is stirred for 4 hours at atemperature of approximately 20° C. then concentrated under reducedpressure at 40° C. The residue is taken up in dichloromethane (7 ml) anda saturated aqueous solution of sodium hydrogen carbonate (3 ml). Afterdecantation and extractions the combined organic phases are washed withsalt water then concentrated under reduced pressure at 40° C.Purification of the residue by flash chromatography on silica gel(eluent: heptane/ethyl acetate 1:1 to 1:9) produces a compound in theform of foam which is dissolved in ethyl acetate (0.5 ml). A solution ofhydrochloric acid (2N in diethyl ether, 2 ml) is added and the mixtureis stirred for 1 hour at a temperature of approximately 20° C. then theprecipitate obtained is filtered and dried in order to produce theexpected compound (28 mg, 55% yield).

MS/LC: calculated MM=521.7; m/z=522.3 (MH+)

According to reaction diagram E and in a fashion analogous to theprocedure described for the synthesis of tert-butyl3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate dihydrochloride, the following compounds were prepared:

in which R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

F. Preparation According to Reaction Diagram F:

The compounds of formula (I) according to the invention in which Arepresents —CH₂—, can be prepared according to the following diagrams Fand F′:

As described in diagram F, the derivative (4) prepared according toreaction diagram A, can be reduced to compound (24) using borane orlithium aluminium hydride in an aprotic solvent such as tetrahydrofuranor diethyl ether at a temperature of 0 to 70° C., for 18 to 24 hours.The dianiline (24) can then be treated by an isothiocyanate in thepresence of a coupling agent supported or not supported on a resin suchas diisopropylcarbodiimide or dicyclohexylcarbodiimide orN-methylcyclohexylcarbodiimide N-methyl polystyrene resin in an inertsolvent such as tetrahydrofuran, methylene chloride, or chloroform at atemperature of 20-70° C. for 2 to 72 hours in order to producederivative (25).

Preparation According to Reaction Diagram F′:

The compounds (25) can also be prepared according to the followingdiagram F′:

As described in diagram F′, the amide (6) prepared according to reactiondiagrams A or B, can be reduced to the corresponding amine (25) usingborane or lithium aluminium hydride in an aprotic solvent such astetrahydrofuran or diethyl ether at a temperature of 0 to 70° C., for 1to 6 hours.

EXAMPLE F′1 6-{[bis(3-methylbutyl)amino]methyl}-1-[3-(dimethylamino)propyl]-N-(4-methoxyphenyl)-1H-benzimidazol-2-amine hydrochloride

A solution of lithium aluminium hydride (0.785 ml; 1 M in THF) is addeddropwise to a solution cooled down to 0° C. of1-[3-(dimethylamino)propyl]-2-[(4-methoxyphenyl)amino]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamideprepared according to reaction diagram A (80 mg, 1 eq) in anhydroustetrahydrofuran (2 ml). The mixture is taken to a temperature of 20° C.then heated at 60° C. for 3 hours. After cooling down to 0° C., thereaction medium is hydrolyzed. After the addition of ethyl acetate,decantation and extractions, the combined organic phases are washed withsalt water, dried over sodium sulphate and concentrated under reducedpressure. Purification by flash chromatography on silica gel (eluent:100% dichloromethane to dichloromethane/methanol 9:1) produces theexpected compound in the form of a base. The corresponding hydrochloridesalt is formed by adding a 1N solution of hydrochloric acid in diethylether (61 mg; 55% yield).

MS/LC: calculated MM=493.7; m/z=494.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.83 (m, 12H), 1.50-1.72 (m, 6H), 2.29 (m,2H), 2.78 (m, 6H), 2.99 (m, 4H), 3.30 (m, 2H), 3.80 (s, 3H), 4.41 (m,4H), 6.90-8.50 (m, 7H), 10.5 (m, 1H), 10.85 (m, 1H), 12.9 (m, 1H).

The following compounds were prepared according to reaction diagrams For F′:

in which R₁R₂N represents one of the radicals below:

in which R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

G. Preparation According to Reaction Diagram G:

The compounds of formula (I) according to the invention in which Arepresents —C(O)—C(R_(a))(R_(b))—, can be prepared according to thefollowing diagram G:

As described in diagram G, the derivative (26) can be alkylated in thepresence of a strong base such as potassium tertbutylate, by anα-chloroester derivative, in an aprotic polar solvent such asdimethylformamide at a temperature of 0-20° C. for 0.5-2 hours, in orderto produce compound (27). The derivative (27) can be optionallyalkylated in the presence of a strong base such as sodium hydride and analkylating agent such as an alkyl iodide in an aprotic solvent such asdimethylformamide at a temperature of 0-20° C. for 1-4 hours, in orderto produce compound (28). The ester (28) can be saponified in thepresence of an inorganic base such as lithium or potassium hydroxide ina mixture of polar solvents such as water and methanol at a temperatureof 20-80° C. for 1-6 hours. The resultant carboxylic acid (29) can becoupled with a primary or secondary amine in the presence of a couplingagent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide(DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)or carbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole(HOBt) in an inert organic solvent such as methylene chloride,tetrahydrofuran or dimethylformamide at ambient temperature for 3 to 24hours. Alternatively the acid (29) can be treated with thionyl or oxalylchloride in an aprotic solvent such as dichloromethane or toluene at atemperature of 40-60° C. for 2-16 hours then the acid chloride thusobtained can react with a primary or secondary amine, in the presence ofa tertiary base such as triethylamine, diisopropylethylamine in anaprotic solvent such as dichloromethane or tetrahydrofuran at atemperature of 0-20° C. over 0.5-4 hours in order to produce the amide(30). Treatment of the fluorinated or chlorinated derivative (30) with aprimary amine in the presence of an inorganic base such as caesium orpotassium carbonate in an inert organic solvent such asdimethylformamide or acetonitrile at a temperature of 20-100° C. for 2to 48 hours leads to the derivative (31). The nitro function of compound(31) is reduced by treatment with tin chloride dihydrate in an inertsolvent such as ethyl acetate or dimethylformamide at a temperature of60-80° C. for 3 to 15 hours, or by catalytic hydrogenation in thepresence of 10% palladium on carbon in an inert solvent such asmethanol, ethanol, ethyl acetate or a mixture of these solvents, at atemperature of 18-25° C., for 2 to 8 hours in order to produce thedianiline (32). The derivative (32) is then treated with anisothiocyanate in the presence of a coupling agent supported or notsupported on a resin such as diisopropylcarbodiimide ordicyclohexylcarbodiimide or N-methylcyclohexylcarbodiimide N-methylpolystyrene resin in an inert solvent such as tetrahydrofuran, methylenechloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hoursin order to produce the derivative (33). Alternatively, the derivative(32) can be treated with an isothiocyanate in an inert solvent such astetrahydrofuran, methylene chloride, chloroform or ethanol at atemperature of 20-80° C. for 1-16 hours then the resultant thiourea canbe treated with methyl iodide or yellow mercury (II) oxide in thepresence of a catalytic quantity of sulphur in a polar solvent such asmethanol or ethanol for 2 to 24 hours at a temperature of 20-80° C. inorder to produce (33). Compound (6) can be isolated either by flashchromatography on silica gel, or by the addition to the reaction mixtureof a nucleophilic reagent supported on a polymer such as for example anaminomethylpolystyrene resin and/or an electrophilic reagent supportedon a polymer such as for example methylisothiocyanate-polystyrene resin,followed by filtration and evaporation of the filtrate.

EXAMPLE G12-{2-[(4-acetylphenyl)amino]-1-[3-(dimethylamino)propyl]-1H-benzimidazol-6-yl}-N,N-diisobutyl-2-methylpropanamidedihydrochloride

Stage 1: ethyl 2-(3-chloro-4-nitrophenyl)propanoate

Potassium tert-butylate (11.22 g, 2 eq) is added to a solution of DMF(80 ml) cooled down to 0° C. A solution of 1-chloro-2-nitrobenzene (7.87g, 1 eq) and ethyl 2-chloropropanoate (7 ml, 1.1 eq) is added dropwiseover 45 minutes to the mixture whilst keeping the reaction temperaturebelow 5° C. At the end of the addition, stirring is maintained for 2hours at 0° C., then the mixture is hydrolyzed at this temperature witha 1N solution of hydrochloric acid and ethyl acetate is added. Afterdecantation and extractions, the combined organic phases are washed withsalt water, dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography on silica gel (eluent:heptane/dichloromethane 8:2 to 6:4) produces the expected compound inthe form of a yellow oil (8.28 g; 64% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.14 (t, 3H), 1.42 (d, 3H), 3.99 (q, 1H),4.08 (m, 2H), 7.52 (AB, 1H), 7.71 (s, 1H), 8.05 (AB, 1H).

Stage 2: ethyl 2-(3-chloro-4-nitrophenyl)-2-methylpropanoate

A solution of ethyl 2-(3-chloro-4-nitrophenyl)propanoate (14.1 g) isadded dropwise to a suspension of sodium hydride (60% in oil, 2.4 g, 1.1eq) in DMF (15 ml), cooled down to 0° C. After stirring for 1 hour atthis temperature, a solution of methyl iodide (3.72 ml, 1.1 eq) in DMF(40 ml) is added dropwise to the mixture. Stirring is continued for 3hours at ambient temperature. The reaction medium is cooled down to 0°C. then ethyl acetate, water saturated with sodium hydrogen carbonateare added dropwise, then water. After decantation and extractions, thecombined organic phases are washed with salt water, dried over Na₂SO₄and concentrated under reduced pressure in order to produce the expectedcompound in the form of an oil which crystallizes. The crystals arewashed with heptane and dried (13.8 g; 94% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.12 (t, 3H), 1.54 (s, 6H), 4.09 (q, 1H),7.50 (AB, 1H), 7.66 (s, 1H), 8.04 (AB, 1H).

Stage 3: 2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid

A 2N solution of potassium hydroxide (18 ml) is added at a temperatureof approximately 20° C. to a solution of ethyl2-(3-chloro-4-nitrophenyl)-2-methylpropanoate (1 g) in methanol (20 ml).The mixture is then heated at 80° C. for 1.5 hours then cooled down toambient temperature. The methanol is evaporated by concentration of themixture under reduced pressure. The remaining aqueous phase is washedwith dichloromethane then cooled down to 0° C. and acidified with aceticacid. After the addition of dichloromethane, decantation andextractions, the combined organic phases are washed with salt water,dried over Na₂SO₄ and concentrated under reduced pressure in order toproduce the expected compound in the form of an oil which crystallizes(852 mg, 95% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.52 (s, 6H), 7.53 (AB, 1H), 7.66 (s, 1H),8.04 (AB, 1H), 12.72 (s, 1H).

Stage 4: 2-(3-chloro-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide

Thionyl chloride (0.54 ml, 4 eq) is added to a solution of2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid (500 mg) indichloromethane (1 ml). The mixture is heated under reflux for 16 hoursthen cooled down to ambient temperature. The solvent is evaporated offunder reduced pressure at 40° C. (co-evaporation with toluene).Diisopropylethylamine (0.42 ml, 1.2 eq) and diisobutylamine (0.36 ml, 1eq) are successively added to a solution of the acid chloride thusobtained in dichloromethane (1 ml), cooled down to 0° C. At the end ofthe addition, stirring is continued for 3 hours at ambient temperaturethen the mixture is concentrated under reduced pressure at 40° C. Theresidue is dissolved in ethyl ether and the organic phase is washedsuccessively with 1N soda, a saturated solution of sodium hydrogencarbonate, salt water then dried over Na₂SO₄ and concentrated underreduced pressure at 40° C. Purification by flash chromatography onsilica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) produces theexpected compound in the form of an oil which crystallizes (0.585 g; 82%yield).

MS/LC: calculated MM=354.9; m/z=355.2 (MH+)

NMR (¹H, 400 MHz, CDCl₃): δ 0.58 (d, 6H), 0.90 (d, 6H), 1.58 (m, 6H),1.74 (m, 1H), 1.95 (m, 1H), 2.65 (d, 2H), 3.27 (d, 2H), 7.30 (AB, 1H),7.44 (s, 1H), 7.91 (AB, 1H).

Stage 5:2-(3-{[3-(dimethylamino)propyl]amino}-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide

A mixture of2-(3-chloro-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (78 mg, 1eq), 3-dimethylaminopropylamine (45 mg, 2 eq) and potassium carbonate(62 mg, 2 eq) in DMF (2 ml) is heated under reflux for 3 hours thencooled down to ambient temperature. The residue is taken up in ethylacetate (20 ml) and water (8 ml). After decantation and extractions, thecombined organic phases are washed with salt water, dried over Na₂SO₄then concentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: 100%dichloromethane to dichloromethane/methanol 8:2) produces the expectedcompound in the form of a yellow oil (44 mg; 48% yield).

MS/LC: calculated MM=420.6; m/z=421.3 (MH+)

NMR (¹H, 400 MHz, CDCl₃): δ 0.60 (d, 6H), 0.90 (d, 6H), 1.57 (m, 6H),1.75 (m, 1H), 1.88 (m, 2H), 1.97 (m, 1H), 2.28 (s, 6H), 2.45 (t, 1H),2.75 (d, 2H), 3.26 (d, 2H), 3.34 (m, 2H), 6.57 (m, 1H), 6.68 (s, 1H),8.15 (m, 1H), 8.49 (m, 1H).

Stage 6:2-(4-amino-3-{[3-(dimethylamino)propyl]amino}phenyl)-N,N-diisobutyl-2-methylpropanamide

2-(3-{[3-(dimethylamino)propyl]amino}-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide(44 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (3 ml),and 10% palladium on carbon (5 mg) are introduced into an autoclave.After stirring for 4 hours under a hydrogen atmosphere (3 bar) at atemperature of approximately 20° C., the catalyst is eliminated byfiltration on celite and the filtrate is concentrated under reducedpressure at 40° C. in order to produce the expected compound in the formof an oil (39 mg; 95% yield).

MS/LC: calculated MM=390.6; m/z=391.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.49 (m, 6H), 0.81 (m, 6H), 1.36 (s, 6H),1.65 (m, 1H), 1.72 (m, 2H), 1.87 (m, 1H), 2.20 (s, 6H), 2.39 (t, 2H),2.81 (m, 2H), 2.97 (t, 2H), 3.11 (m, 2H), 4.56 (m, 2H), 6.18 (s, 1H),6.30 (AB, 1H), 6.48 (AB, 1H).

Stage 7:2-{2-[(4-acetylphenyl)amino]-1-[3-(dimethylamino)propyl]-1H-benzimidazol-6-yl}-N,N-diisobutyl-2-methylpropanamidedihydrochloride

4-acetylphenyl isothiocyanate (14 mg, 1.2 eq) andN-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; charge 1.9 mmol/g; 210 mg, 4 eq) are successively added toa solution of2-(4-amino-3-{[3-(dimethylamino)propyl]amino}phenyl)-N,N-diisobutyl-2-methylpropanamide(39 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated underreflux for 17 hours then cooled down to ambient temperature andfiltered. The filtrate is concentrated under reduced pressure at 40° C.Purification of the residue by flash chromatography on silica gel(eluent: 100% dichloromethane to dichloromethane/methanol 9:1) producesthe expected compound in form of a base (409 mg; 60% yield). Thecorresponding hydrochloride salt is formed by adding a 1N solution ofhydrochloric acid in ether. The precipitate obtained is filtered anddried in order to produce the expected dihydrochloride compound (51 mg,85% yield).

MS/LC: calculated MM=533.7; m/z=534.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.40 (m, 6H), 0.82 (m, 6H), 1.53 (s, 6H),1.64 (m, 1H), 1.89 (m, 1H), 2.21 (m, 2H), 2.59 (s, 3H), 2.75 (m, 8H),3.15 (m, 2H), 3.25 (m, 2H), 4.60 (t, 2H), 7.10 (AB, 1H), 7.41 (AB, 1H),7.56 (s, 1H), 7.82 (m, 2H), 8.05 (m, 2H), 10.79 (m, 1H), 11.4 (m, 1H).

According to reaction diagram G, the following compounds were prepared:

in which R₁R₂N represents one of the radicals below:

R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

A subject of the invention is also a process for the preparation of acompound of formula (I) as defined above, characterized in that thecompound of general formula:

in which A, X, R₁, R₂, R₄ have the meaning indicated above, is treatedwith an isothiocyanate of general formula R₃N═C═S in which R₃ has themeaning indicated above, in the presence of a coupling agent or ofyellow mercury (II) oxide in the presence of sulphur, for a period of 3to 48 hours, in a protic or aprotic solvent, at a temperature of 50 to80° C.

The coupling agent can be supported such as N-methylcyclohexylcarbodiimide N-methyl polystyrene resin or not supported such asdiisopropylcarbodiimide, diethylcarbodiimide ordicyclohexylcarbodiimide. A protic solvent such as methanol or ethanolor an aprotic solvent such as tetrahydrofuran or acetonitrile can beused.

A subject of the invention is also a compound of general formula (II)

in racemic or enantiomeric form or any combinations of these forms andin which:A represents —CH₂—, —C(O)—, —C(O)—C(R_(a))(R_(b))—;X represents —C— or —N—;R_(a) and R_(b) represent, independently, the hydrogen atom or a(C₁-C₆)alkyl radical;R₁ and R₂ represent, independently, the hydrogen atom, a (C₁-C₈)alkylradical optionally substituted by hydroxy, (C₂-C₆)alkenyl or a radicalof formula —(CH₂)_(n)—X₁;X₁ represents (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, adamantyl,heterocycloalkyl, aryl or heteroaryl,

-   -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n′)—V₁—Y₁ halo,        nitro and cyano;    -   V₁ represents —O—, —S— or a covalent bond;    -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals; or aryl;    -   n represents an integer from 0 to 6 and n′ an integer from 0 to        2 (it being understood that when n is equal to 0, then X₁        represents neither the hydroxy radical nor the alkoxy radical);        or R₁ and R₂ form together with the nitrogen atom to which they        are attached, a heterobicycloalkyl or a heterocycloalkyl        optionally substituted by one or more identical or different        substituents chosen from: hydroxy, (C₁-C₆)alkyl,        (C₁-C₆)hydroxyalkyl, (C₁-C₆)alkoxy-carbonyl, —C(O)NV₁′Y₁′ with        V₁′ and Y₁′ independently representing the hydrogen atom or a        (C₁-C₆)alkyl, and heterocycloalkyl; or R₁ and R₂ form together a        radical of formula:

R₃ represents —(CH₂)_(p)-Z₃ or —C(O)-Z′₃

-   -   Z₃ represents a (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy,        (C₁-C₆)alkoxy-carbonyl, (C₃-C₇)cycloalkyl, heterocycloalkyl,        aryl or heteroaryl radical,    -   the (C₃-C₇) cycloalkyl and heterocycloalkyl radicals being        optionally substituted by (C₁-C₆)alkyl,    -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from: halo, nitro,        azido or —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—,        —C(O)—NR₁₃—, —NH—C(O)—NR′₃— or a covalent bond;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   or Z₃ represents a radical of formula

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃—, —NH—C(O)—,        —NH—C(O)—NR₁₃— or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;    -   p, p′ and p″ represent, independently, an integer from 0 to 4;        R₄ represents a radical of formula —(CH₂)_(s)—R′₄        R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl or        aralkyl; a heteroaryl containing at least one nitrogen atom and        optionally substituted by (C₁-C₆)alkyl; or a radical of formula        —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl optionally        substituted by one or more identical or different substituents        chosen from: (C₁-C₆)alkoxy, (C₁-C₆)alkylthio and hydroxy;        (C₂-C₆)alkenyl; (C₃-C₇)cycloalkyl optionally substituted by one        or more identical or different (C₁-C₆)alkyl substituents;        cyclohexene; heteroaryl; aryl optionally substituted by one or        more identical or different radicals chosen from:        —(CH₂)_(s″)—V₄—Y₄, hydroxy, halo, nitro and cyano;        -   V₄ represents —O—, —S—, —NH—C(O)—, —NV₄′— or a covalent            bond;        -   Y₄ represents a hydrogen atom or a (C₁-C₆)alkyl radical            optionally substituted by one or more identical or different            halo radicals;        -   V₄′ represents a hydrogen atom or a (C₁-C₆)alkyl;        -   s″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   and s′ represent, independently, an integer from 0 to 6;        and when R₃ represents —C(O)-Z′₃ and R₄ represents a radical of        formula —(CH₂)_(s)—NW₄W′₄ and W₄ and W′₄ represent,        independently, the hydrogen atom or the (C₁-C₆)alkyl radical,        then —(CH₂)_(s) represents neither the ethylene radical nor the        —(CH₂)—CH((C₁-C₄)alkyl)-radical;

Preferably, the invention relates to compounds of formula II as definedabove and in which

A represents —C(O)— and X represents —C—;R₁ and R₂ represent, independently, a hydrogen atom, a (C₁-C₈)alkylradical optionally substituted by hydroxy, (C₂-C₆)alkenyl or a radicalof formula —(CH₂)_(n)—X₁;X₁ represents (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, aryl or heteroaryl,

-   -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from:        —(CH₂)_(n′)—V₁—Y₁, halo;    -   V₁ represents —O— or a covalent bond;    -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals; or aryl;        or R₁ and R₂ form together with the nitrogen atom to which they        are attached, a heterocycloalkyl optionally substituted by one        or more identical or different substituents chosen from:        hydroxy, (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl,        (C₁-C₆)alkoxy-carbonyl, —C(O)NV₁′-Y₁′ with V₁′ and Y₁′        independently representing the hydrogen atom or a (C₁-C₆)alkyl,        and heterocycloalkyl; or R₁ and R₂ form together a radical of        formula:

R₃ represents —(CH₂)_(p)-Z₃ or —C(O)-Z′₃

-   -   Z₃ represents a (C₁-C₆)alkoxy-carbonyl, (C₃-C₇)cycloalkyl,        heteroaryl, or aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro or —(CH₂)_(p)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃—,        —NH—C(O)—, —NH—C(O)—NR₁₃— or a covalent bond;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   or Z₃ represents a radical of formula

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O— or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;    -   p is equal to 0 or 1, and p′ and p″ are equal to 0;

R₄ represents a radical of formula —(CH₂)_(n)—R′₄

-   -   R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl or        benzyl; a heteroaryl containing at least one nitrogen atom; or a        radical of formula —NW₄W′₄;    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl        or aryl;        and more particularly        the cycloalkyl radical is chosen from the cyclopropyl,        cyclohexyl and cycloheptyl radicals,        the heterocycloalkyl radical is chosen from the pyrrolidinyl,        piperidinyl, morpholinyl, piperazinyl, azacycloheptyl,        azacyclooctyl and decahydro-isoquinolinyl radicals,        the aryl radical is the phenyl radical,        the heteroaryl radical is chosen from the furyl, pyridyl and        imidazolyl radicals,        or a pharmaceutically acceptable salt thereof.

Very preferably, the invention also relates to compounds of formula IIas defined above and in which

A represents —C(O)— and X represents —C—;R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;R₃ represents —(CH₂)_(p)-Z₃

-   -   Z₃ represents a phenyl radical optionally substituted by one or        more identical or different substituents chosen from: nitro or        —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃—, NH—C(O)—,        —NH—C(O)—NR₁₃—;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical;    -   R′₃ represents the hydrogen atom or a (C₁-C₆)alkoxy radical;    -   p is equal to 0 or 1; p′ is equal to 0;        R₄ represents a radical of formula —(CH₂)_(s′)—R′₄        R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄;    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom or (C₃-C₇)cycloalkyl;    -   s represents an integer from 2 to 4; s′ represents an integer        from 0 to 4;        and more particularly the heterocycloalkyl radical represented        by R′₄ is the pyrrolidinyl, piperidinyl, morpholinyl or        piperazinyl radical, and the cycloalkyl represented by Z₄ is        cyclohexyl;        or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula II asdefined above and in which

A represents —C(O)—C(R_(a))(R_(b))—; X represents —C—;R_(a) and R_(b) represent, independently, a (C₁-C₆)alkyl radical;R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;R₃ represents —(CH₂)_(p)-Z₃

-   -   Z₃ represents a phenyl radical optionally substituted by one or        more identical or different substituents of formula        —(CH₂)_(p)—V₃—Y₃;    -   V₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃—,        —NH—C(O)—NR₁₃—;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical;    -   R′₃ represents a (C₁-C₆)alkyl or (C₁-C₆)alkoxy radical;    -   p and p′ are equal to 0;        R₄ represents a radical of formula —(CH₂)_(s)—R′₄        R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, the phenyl radical or a        heteroaryl;    -   s represents an integer from 2 to 4; s′ represents an integer        from 0 to 4;        or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula II asdefined above and in which

A represents —CH₂—; X represents —C—;R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;R₃ represents —(CH₂)_(p)-Z₃

-   -   Z₃ represents a phenyl radical optionally substituted by one or        more identical or different substituents of formula        —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR₁₃—,        —NH—C(O)—NR₁₃—;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical;    -   R′₃ represents a (C₁-C₆)alkyl or (C₁-C₆)alkoxy radical;    -   p and p′ are equal to 0;        R₄ represents a radical of formula —(CH₂)_(s)—R′₄        R′₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom;    -   s represents an integer from 2 to 4; s′ represents an integer        from 0 to 4;        or a pharmaceutically acceptable salt thereof.

The compounds I and II of the present invention have usefulpharmacological properties. It has thus been discovered that thecompounds I and II of the present invention have a good affinity forcertain sub-types of melanocortin receptors, in particular the MC4receptors.

The compounds of the present invention can thus be used in differenttherapeutic applications. They can advantageously be used for treatingthe pathological states or diseases in which one or more melanocortinreceptors are involved such as inflammatory conditions, weight disorders(obesity, cachexia, anorexia), sexual activity disorders (erectivedisorders), pain, but also mental health problems (anxiety, depression),drug addiction, skin diseases (acne, dermatoses, melanomas). Hereafter,in the experimental part, an illustration will be found of thepharmacological properties of the compounds of the invention.

A subject of the present Application is also pharmaceutical compositionscontaining, as active ingredient, at least one product of formula I asdefined above, as well as the pharmaceutically acceptable salts of saidproduct of formula I, in combination with a pharmaceutically acceptablesupport.

By pharmaceutically acceptable salt, is understood in particularaddition salts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or of organicacids such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.Also within the scope of the present invention, when they can be used,the salts formed from bases such as sodium or potassium hydroxide. Forother examples of pharmaceutically acceptable salts, reference can bemade to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

A subject of the present Application is also the use of the compoundsaccording to the present invention, for the preparation of a medicamentfor the treatment of weight disorders such as obesity, cachexia and moreparticularly cancerous cachexia, AIDS cachexia, old-age cachexia,cardiac cachexia, renal cachexia, cachexia in rheumatoid arthritis, andanorexia, the treatment of pain and more particularly neuropathic pain,mental health problems such as anxiety and depression, sexual activitydisorders such as erective disorders.

The pharmaceutical composition can be in the form of a solid, forexample, powders, granules, tablets, gelatin capsules or suppositories.Appropriate solid supports can be, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

A subject of the present invention is also the use of a compound ofgeneral formula (I′)

in racemic or enantiomeric form or any combinations of these forms andin which:A′ represents —CH₂— —C(O)—, —C(O)—C(R_(a))(R_(b))—;X′ represents —CH—;R_(a) and R_(b) represent, independently, the hydrogen atom or a(C₁-C₆)alkyl radical;R′₁ represents the hydrogen atom; a (C₁-C₈)alkyl radical optionallysubstituted by hydroxy or one or more identical or different haloradicals; (C₂-C₆)alkenyl; or a radical of formula —(CH₂)_(n)—X₁;R′₂ represents a (C₁-C₈)alkyl radical optionally substituted by hydroxyor one or more identical or different halo radicals; (C₂-C₆)alkenyl; ora radical of formula —(CH₂)_(n)—X₁;each X₁ independently represents (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,adamantyl, heterocycloalkyl, aryl or heteroaryl,

-   -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n′)—V₁—Y₁ halo,        nitro, cyano and aryl;    -   V₁ represents —O—, —S— or a covalent bond;    -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals;    -   n represents an integer from 0 to 6 and n′ an integer from 0 to        2 (it being understood that when n is equal to 0, then X₁ does        not represent the alkoxy radical)        or R₁ and R₂ form together with the nitrogen atom to which they        are attached, a heterobicycloalkyl or a heterocycloalkyl        optionally substituted by one or more identical or different        substituents chosen from: hydroxy, (C₁-C₆)alkyl optionally        substituted by hydroxy, (C₁-C₆)alkoxy-carbonyl, heterocycloalkyl        and —C(O)NV₁′Y₁′ with V₁′ and Y₁′ independently representing the        hydrogen atom or a (C₁-C₆)alkyl; or R₁ and R₂ form together a        radical of formula:

R′₃ represents -Z₃, C(R_(Z3))(R′_(Z3))-Z₃,—C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ or —C(O)-Z′₃

-   -   R_(Z3) and R′_(Z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z₃ represents Z_(3a), Z_(3b), Z_(3c), Z_(3d), or Z_(3e);    -   Z_(3a) represents a (C₁-C₆)alkyl radical;    -   Z_(3b) represents a (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,        (C₁-C₆)alkylamino or di((C₁-C₆)alkyl)amino radical;    -   Z_(3c) represents an aryl or heteroaryl radical;    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkylamino-carbonyl, di((C₁-C₆)alkyl)amino-carbonyl,        (C₁-C₆)alkyl-C(O)—NH—, (C₃-C₇)cycloalkyl, heterocycloalkyl        radical;    -   the (C₃-C₇) cycloalkyl and heterocycloalkyl radicals being        optionally substituted by one or more identical or different        substituents chosen from: halo, nitro, (C₁-C₆)alkoxy optionally        substituted by one or more identical or different halo radicals,        (C₁-C₆)alkyl optionally substituted by one or more identical or        different halo radicals, (C₁-C₆)alkyl-carbonyl,        (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkylamino-carbonyl, di((C₁-C₆)alkyl)amino-carbonyl and        oxy,    -   the aryl and heteroaryl radicals being optionally substituted by        one or more identical or different substituents chosen from:        halo, cyano, nitro, azido, oxy,        (C₁-C₆)alkoxy-carbonyl-(C₁-C₆)alkenyl,        (C₁-C₆)alkylamino-carbonyl-(C₁-C₆)alkenyl, —SO₂—NR₃₁R₃₂,        heterocycloalkyl, heteroaryl or —(CH₂)_(p′)—V₃—Y₃;    -   R₃₁ and R₃₂ form together with the nitrogen atom to which they        are attached, a heterocycloalkyl;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —O—C(O)—, —SO₂—,        —SO₂NH—, —N′R₃—SO₂—, —NR′₃—, —NR′₃—C(O)—, —C(O)—NR′₃—,        —NH—C(O)—NR′₃— or a covalent bond;    -   Y₃ represents the hydrogen atom; a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals; an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro, (C₁-C₆)alkyl and (C₁-C₆)alkoxy; or an aryl-(C₁-C₆)alkyl        radical optionally substituted by one or more identical or        different substituents chosen from: halo, nitro, (C₁-C₆)alkyl        and (C₁-C₆)alkoxy;    -   Z_(3e) represents a radical of formula

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′₃, —NH—C(O)—NR′₃        or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;    -   p represents an integer from 1 to 4; p′ and p″ represent,        independently, an integer from 0 to 4;        R₄ represents a radical of formula —(CH₂)_(s)—R′₄;        R′₄ represents the guanidine radical; a heterocycloalkyl        containing at least one nitrogen atom and optionally substituted        by (C₁-C₆)alkyl or aralkyl; a heteroaryl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a        radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl optionally        substituted by one or more identical or different substituents        chosen from: (C₁-C₆)alkoxy, (C₁-C₆)alkylthio and hydroxy;        (C₂-C₆)alkenyl; (C₃-C₇)cycloalkyl optionally substituted by one        or more identical or different (C₁-C₆)alkyl substituents;        cyclohexene; heteroaryl and aryl;        -   the aryl and heteroaryl radicals being optionally            substituted by one or more identical or different radicals            chosen from formula —(CH₂)_(s″)—V₄—Y₄, hydroxy, halo, nitro            and cyano;            -   V₄ represents —O—, —S—, —NH—C(O)—, —NV′₄ or a covalent                bond;            -   Y₄ represents a hydrogen atom or a (C₁-C₆)alkyl radical                optionally substituted by one or more identical or                different halo radicals;            -   V₄′ represents a hydrogen atom or a (C₁-C₆)alkyl;            -   s″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   s and s′ represent, independently, an integer from 0 to 6; or a        pharmaceutically acceptable salt thereof;        for the preparation of a medicament for the treatment of weight        disorders, mental health problems, pain, or sexual activity        disorders.

A subject of the present invention is more particularly the use of acompound of general formula (I′) as defined above, characterized in that

-   -   R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;    -   R₃ represents Z_(3c) and Z_(3c) represents a phenyl or naphthyl        radical, each substituted at least by cyano;    -   R₄ represents a radical of formula —(CH₂)_(s)—R′₄ with R′₄        representing the pyrrolidinyl or piperidinyl radical; or a        radical of formula —NW₄W′₄;        -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;        -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄ with Z₄            representing the hydrogen atom;        -   s represents an integer from 2 to 4; s′ represents an            integer from 0 to 4;            or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or the glycols, as well astheir mixtures, in varying proportions, in water, added topharmaceutically acceptable oils or greases. The sterile liquidcompositions can be used for intramuscular, intraperitoneal orsub-cutaneous injections and the sterile compositions can also beadministered by intravenous route.

All the technical and scientific terms used in the present text have themeaning known to a person skilled in the art. Moreover, all the patents(or patent applications) as well as the other bibliographical referencesare incorporated by way of reference.

Experimental Part:

The compounds according to the invention obtained according to theprocedures of Examples A, B, C, C′, D, E, F, F′ and G describedpreviously, are set out in the table below.

The compounds are characterized by their retention times (rt) and theirmolecular peak determined by mass spectrometry (MH+).

For the mass spectrometry, a single quadripole mass spectrometer(Micromass, Platform model) equipped with an electrospray source is usedwith a resolution of 0.8 Da at 50% valley. A calibration is carried outmonthly between the masses 80 and 1000 Da using a calibrating mixture ofsodium iodide and rubidium iodide in solution in an isopropanol/watermixture (1/1 Vol.).

For the liquid chromatography, a Waters system including an in-linedegasser, a Waters 600 quaternary pump, a Gilson 233 plate samplinginjector and a Waters PAD 996 UV detector, is used.

The elution conditions used are the following:

Eluent: A water+0.04% trifluoroacetic acid; B acetonitrile

T (minutes) A % B % 1 95 5 8.5 5 95 10.5 5 95 10.6 95 5 14.9 95 5 15.095 5Flow rate: 1 ml/min; Injection: 10 μl; Column: Uptisphere ODS 3 μm75*4.6 mm i.d.

These examples are presented in order to illustrate the procedures aboveand should in no event be considered as a limit to the scope of theinvention.

Examples Molecular structures [M + H]+ rt (min) 1

512.3 7.8 2

582.3 8.0 3

490.5 7.5 4

491.4 6.9 5

508.4 7.6 6

574.4 8.0 7

566.4 8.1 8

626.4 8.2 9

540.3 8.2 10

454.3 7.2 11

467.9 7.3 12

482.3 7.4 13

496.1 7.5 14

484.5 7.0 15

484.3 7.0 16

498.3 7.1 17

482.3 7.5 18

496.2 7.6 19

470.2 7.0 20

498.3 7.2 21

469.1 6.2 22

537.1 6.8 23

551.0 6.9 24

540.2 7.4 25

540.0 7.4 26

541.0 7.3 27

566.9 7.3 28

526.0 7.2 29

522.3 7.7 30

452.2 7.2 31

466.1 7.3 32

452.3 7.8 33

422.3 7.7 34

440.3 7.8 35

490.3 8.3 36

464.3 8.0 37

468.3 7.9 38

458.3 8.0 39

490.3 8.9 40

482.3 7.9 41

466.3 7.8 42

467.3 8.3 43

436.3 7.8 44

436.3 7.8 45

450.3 8.0 46

490.3 8.2 47

497.3 8.5 48

464.3 8.1 49

468.3 8.0 50

462.4 8.0 51

452.4 7.8 52

450.4 8.0 53

500.2 8.2 54

514.3 8.2 55

484.2 8.7 56

484.2 9.1 57

484.2 9.0 58

495.3 8.9 59

464.3 8.7 60

464.3 8.9 61

480.3 8.7 62

464.3 8.9 63

450.3 8.7 64

484.2 8.4 65

528.2 8.5 66

468.3 8.2 67

464.3 8.1 68

495.3 9.1 69

480.3 8.1 70

496.3 8.3 71

518.2 9.0 72

534.2 8.7 73

492.3 8.4 74

508.3 8.5 75

525.3 8.9 76

478.2 8.5 77

522.2 8.6 78

522.2 8.4 79

506.2 8.2 80

492.2 8.5 81

508.2 8.6 82

522.3 8.8 83

494.2 8.7 84

529.3 8.5 85

543.3 8.7 86

545.3 8.6 87

506.3 8.5 88

507.3 7.9 89

543.3 8.5 90

557.3 8.7 91

559.3 8.7 92

558.3 8.0 93

494.3 8.1 94

507.2 8.0 95

521.2 8.0 96

549.3 8.2 97

522.3 8.6 98

564.3 8.9 99

564.3 9.1 100

562.3 8.8 101

562.3 8.8 102

576.3 8.9 103

590.3 9.0 104

578.3 8.7 105

591.3 8.5 106

456.2 8.0 107

500.1 8.0 108

440.2 7.7 109

490.2 8.4 110

478.3 8.2 111

548.1 8.1 112

479.2 7.6 113

478.2 8.1 114

637.3 8.8 115

653.3 9.0 116

547.3 8.8 117

563.3 9.0 118

610.4 9.1 119

626.4 9.3 120

520.3 8.5 121

534.3 8.7 122

536.3 8.6 123

550.3 8.2 124

535.3 8.0 125

506.3 8.4 126

548.3 8.6 127

548.3 8.8 128

546.3 8.6 129

546.3 8.6 130

560.3 8.6 131

574.3 8.7 132

562.3 8.5 133

575.3 8.3 134

522.3 8.2 135

521.2 8.1 136

563.2 8.2 137

563.2 8.3 138

561.2 8.2 139

561.2 8.2 140

575.2 8.2 141

589.2 8.3 142

577.2 8.1 143

594.4 8.8 144

535.4 8.0 145

564.4 9.5 146

588.4 9.2 147

456.2 7.2 148

484.3 7.5 149

512.2 7.8 150

470.3 7.3 151

470.2 7.4 152

498.3 7.6 153

540.2 8.1 154

496.3 7.6 155

480.3 7.4 156

516.0 7.0 157

516.2 7.2 158

522.3 7.9 159

590.2 8.0 160

608.5 9.2 161

624.5 9.4 162

623.5 8.5 163

534.3 8.7 164

533.3 8.0 165

535.4 8.0 166

564.4 9.5 167

508.2 8.2 168

474.3 8.0 169

484.4 8.2 170

498.4 8.4 171

526.3 8.4 172

540.3 8.5 173

482.3 8.1 174

566.4 8.1 175

520.2 8.6 176

534.2 8.7 177

534.2 8.7 178

560.2 8.9 179

574.2 9.0 180

588.2 9.1 181

532.2 8.6 182

494.4 7.5 183

534.4 8.1 184

504.4 8.4 185

562.2 8.9 186

546.2 8.7 187

562.2 8.9 188

508.2 8.2 189

494.4 7.5 190

474.3 8.0 191

484.4 8.2 192

498.4 8.4 193

526.3 8.4 194

540.3 8.5 195

482.3 8.1 196

566.4 8.1 197

602.3 9.2 198

550.3 8.1 199

549.3 7.8 200

564.4 8.1 201

606.4 8.2 203

611.4 7.4 204

478.4 7.5 205

492.4 7.5 206

508.3 7.6 207

507.3 7.3 208

522.3 7.4 209

610.3 8.7 210

624.4 8.7 211

640.4 8.8 212

639.9 8.3 213

654.4 8.5 214

514.4 8.2 215

528.4 8.2 216

560.4 8.2 217

592.4 8.1 218

594.3 8.1 219

590.4 8.4 220

532.3 8.4 221

548.2 8.6 222

547.4 8.0 223

550.4 8.5 224

542.4 8.2 225

604.5 8.3 226

528.4 7.9 227

556.5 8.1 228

556.5 8.0 229

590.4 8.4 230

532.4 8.6 231

546.4 8.6 232

548.3 8.5 233

547.4 7.9 234

533.4 7.9 235

532.5 8.7 236

548.4 8.8 237

547.5 8.1 238

533.4 8.0 239

532.4 8.1 240

548.4 8.3 241

547.4 7.7 242

533.4 7.7 243

632.5 8.3 244

556.4 8.1 245

570.4 8.1 246

584.5 8.2 247

548.4 7.5 248

472.4 7.2 249

486.4 7.3 250

500.4 7.3 251

618.5 8.7 252

602.5 8.6 253

617.5 8.1 254

603.5 8.1 255

534.4 7.6 256

518.4 7.5 257

533.4 7.3 258

519.4 7.2 259

518.4 8.1 260

534.4 8.2 261

533.4 7.7 262

519.4 7.7 263

562.4 7.8 264

486.3 7.6 265

500.4 7.6 266

514.4 7.7 267

562.4 8.2 268

546.4 8.1 269

561.4 7.8 270

547.4 7.8 271

570.4 8.7 272

542.4 8.7 273

554.4 8.6 274

513.4 8.3 275

527.4 8.4 276

556.4 8.6 277

556.4 8.8 278

576.4 7.9 279

500.4 7.6 280

514.4 7.6 281

528.5 7.7 282

548.4 8.7 283

597.4 8.9 284

570.4 8.9 285

597.4 8.7 286

567.4 8.5 287

554.4 8.4 288

538.3 8.7 289

522.4 8.6 290

562.4 8.5 291

592.4 8.6 292

574.4 8.6 293

560.4 8.7 294

600.3 9.2 295

562.4 8.5 296

546.3 8.9 297

562.3 9.1 298

561.3 8.5 299

547.3 8.5 300

576.4 8.6 301

500.4 8.4 302

514.4 8.4 303

528.4 8.4 304

590.4 8.5 305

575.4 8.1 306

589.4 8.2 307

534.5 7.7 308

534.5 7.8 309

562.5 7.9 310

546.5 7.8 311

556.4 8.2 312

508.5 7.7 313

524.3 7.5 314

556.4 7.5 315

540.3 7.5 316

539.5 7.9 317

510.4 8.1 318

494.4 8.0 319

542.4 8.1 320

526.4 7.8 321

528.4 8.3 322

500.4 8.4 323

514.4 8.4 324

570.4 8.8 325

506.4 7.3 326

506.4 7.3 327

534.4 7.4 328

518.4 7.3 329

528.3 7.6 330

548.3 7.3 331

486.3 7.0 332

480.4 7.1 333

592.4 8.1 334

634.3 9.2 335

577.4 9.0 336

584.3 8.4 337

591.4 8.3 338

610.3 8.4 339

518.4 7.4 340

534.3 7.5 341

533.3 7.2 342

519.3 7.1 343

544.3 7.8 344

486.3 8.1 345

506.5 7.3 346

518.5 7.5 347

544.4 7.9 348

528.4 7.7 349

506.5 7.4 350

534.4 7.4 351

518.4 7.4 352

534.4 7.6 353

533.5 7.3 354

519.4 7.3 355

486.4 7.2 356

500.4 7.2 357

528.5 7.3 358

548.4 7.4 359

496.4 7.3 360

538.5 8.3 361

522.5 8.2 362

494.5 8.0 363

510.5 8.1 364

562.5 8.1 365

520.5 8.1 366

569.4 8.2 367

561.5 7.9 368

574.5 9.0 369

589.6 8.3 370

562.5 8.4 371

589.6 8.1 372

646.4 9.9 373

524.4 8.7 374

496.4 8.3 375

566.4 9.9 376

534.4 8.2 377

561.4 7.9 378

524.4 8.4 379

506.4 8.1 380

518.4 8.4 381

532.4 8.6 382

534.4 8.5 383

519.4 7.9 384

533.4 7.9 385

547.4 7.9 386

555.3 8.2 387

482.5 8.2 388

482.3 8.0 389

496.4 8.1 390

582.4 10.3 391

556.5 8.4 392

534.4 8.4 393

560.4 9.0 394

547.4 8.2 395

583.4 8.5 396

548.4 8.4 397

576.4 8.4 398

575.5 8.1 399

508.4 8.3 400

524.4 8.4 401

540.4 8.1 402

553.5 8.1 403

530.4 8.4 404

502.4 8.1 405

520.4 8.2 406

548.4 8.2 407

547.4 7.9 408

480.4 8.0 409

496.4 8.1 410

512.4 7.8 411

525.4 7.9 412

548.4 8.6 413

560.4 8.6 414

576.4 8.8 415

562.4 8.5 416

611.4 8.3 417

561.4 8.2 418

546.6 8.1 419

560.6 8.3 420

532.6 8.0 421

574.4 8.3 422

564.6 8.7 423

618.6 9.9 424

602.6 9.1 425

596.6 8.9 426

610.7 8.3 427

665.7 9.6 428

558.7 8.7 429

562.6 8.4 430

576.6 8.5 431

568.6 8.6 432

557.6 8.5 433

590.3 9.3 434

562.3 8.6 435

610.3 9.0 436

624.4 9.0 437

594.3 9.1 438

543.3 9.3 439

563.2 9.7 440

561.3 8.4 441

559.3 8.8 442

582.3 8.8 443

576.2 8.5 444

558.3 8.6 445

526.3 8.3 446

585.3 8.6 447

625.4 8.3 448

618.4 9.6 449

552.4 8.8 450

536.4 8.5 451

596.3 8.9 452

589.5 8.2 453

616.5 9.1 454

603.5 8.3 455

584.5 8.0 456

585.4 8.6 457

557.4 8.5 458

600.4 8.5 459

622.4 9.1 460

601.4 8.7 461

623.4 9.0 462

594.4 8.6 463

573.4 8.3 464

595.3 8.7 465

519.4 8.1 466

548.4 8.4 467

548.4 8.5 468

576.4 9.1 469

596.4 8.9 470

549.3 9.5 471

582.3 8.8 472

596.4 8.2 473

597.4 8.2 474

602.4 9.0 475

571.4 8.5 476

562.4 8.4 477

568.3 8.3 478

582.3 8.5 479

535.4 9.1 480

547.3 7.8 481

557.4 8.2 482

582.3 7.9 483

583.3 7.8 484

548.4 8.2 485

534.4 8.2 486

525.4 7.6 487

527.5 7.5 488

541.4 7.5 489

562.4 8.7 490

534.4 8.2 491

588.4 8.7 492

538.3 8.3 493

588.3 8.5 494

546.4 8.2 495

588.3 8.5 496

573.4 7.9 497

581.4 8.5 498

555.4 8.4 499

556.3 8.2 500

566.4 8.7 501

596.4 8.6 502

560.3 8.3 503

592.3 8.8 504

505.4 7.7 505

491.4 7.9 506

560.3 8.4 507

550.3 8.3 508

596.4 8.7 509

540.3 8.5 510

566.3 8.5 511

616.4 8.7 512

616.4 8.7 513

578.3 8.6 514

624.4 9.0 515

601.4 8.1 516

609.4 8.8 517

583.4 8.7 518

584.4 8.4 519

533.4 7.8 520

574.4 8.4 521

588.3 8.5 522

588.3 8.6 523

568.4 8.7 524

620.4 9.1 525

610.4 9.0 526

622.4 9.0 527

611.4 8.7 528

582.3 8.7 529

594.4 8.6 530

583.3 8.3 531

475.3 8.7 532

493.3 8.0 533

465.3 7.8 534

575.3 8.1 535

541.5 8.0 536

518.4 8.2 537

490.4 8.0 538

504.3 8.0 539

532.3 8.3 540

508.3 7.9

Pharmacological Study

The affinity of the compounds of the present invention for the differentsub-types of melanocortin receptors was measured according to proceduresanalogous to those described below for the MC4 receptors.

Study of the Affinity of the Compounds for the MC4 Receptors ofMelanocortins:

The affinity of the compounds of the invention for the MC4 receptors isdetermined by measuring the inhibition of the binding of [¹²⁵I]-[Nle⁴,D-Phe⁷]-α-MSH to membrane preparations of transfected CHO-K1 cells.

The CHO-K1 cells expressing in a stable fashion the human MC4 receptorsare cultured in an RPMI 1640 medium containing 10% of foetal calf serum,2 mM of glutamine, 100 U/ml of penicillin, 0.1 mg/ml of streptomycin and0.5 mg/ml of G418. The cells are collected with 0.5 mM of EDTA andcentrifuged at 500 g for 5 minutes at 4° C. The pellet is resuspended ina phosphate buffered saline (PBS) medium and centrifuged at 500 g for 5minutes at 4° C. The pellet is resuspended in a Tris 50 mM buffer mediumat pH 7.4 and centrifuged at 500 g for 5 minutes at 4° C. The cells arelysed by sonication and centrifuged at 39,000 g for 10 minutes at 4° C.The pellet is resuspended in the Tris 50 mM buffer medium at pH 7.4 andcentrifuged at 50,000 g for 10 min at 4° C. The membranes obtained inthis last pellet are stored at −80° C.

The measurement of the competitive inhibition of the binding of[¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH to the MC4 receptors is carried out induplicate using polypropylene 96-well plates. The cell membranes (50 μgof proteins/well) are incubated with [¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH (0.5nM) for 90 minutes at 37° C. in a Tris-HCl 50 mM buffer medium, pH 7.4,comprising 0.2% of bovine serum albumin (BSA), 5 mM of MgCl₂, and 0.1mg/ml of bacitracin.

The bonded [¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH is separated from the free[¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH by filtration through GF/C glass fibrefilters (Unifilter, Packard) pre-impregnated with 0.1% ofpolyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filtersare washed with Tris-HCl 50 mM buffer, pH 7.4 at 0-4° C. and theradioactivity present is determined using a counter (Packard Top Count).

The specific binding is obtained by subtracting the non-specific binding(determined in the presence of 0.1 μM of Nle⁴, D-Phe⁷-α-MSH) from thetotal binding. The data are analyzed by computer-aided non-linearregression (MDL) and the values of the inhibition constants (Ki) aredetermined.

The agonist or antagonist activity of the MC4 receptors of the compoundsof the present invention was determined by measuring the production ofcyclic AMP by the CHO-K1 cells transfected by the MC4 receptor.

Measurement of the Production of Intracellular Cyclic Amp Via the MC4Receptors:

The CHO-K1 cells expressing the MC4 receptors of the melanocortins arecultured in 384-well plates in an RPMI 1640 medium with 10% of fetalcalf serum and 0.5 mg/ml of G418. The cells are washed twice with 50 μlof RPMI medium comprising 0.2% BSA and 0.5 mM of3-isobutyl-1-methylxanthine (IBMX).

In order to measure the agonist effect of a compound, the cells areincubated for 5 minutes at 37° C. in the presence of 0.5 mM of IBMX,then stimulation of the production of cyclic AMP is obtained by addingthe compound at concentrations comprised between 1 pM and 10 μM induplicate for 20 minutes at 37° C. The antagonist effect of a compoundis measured by inhibiting stimulation of the production of cyclic AMPinduced by Nle⁴, D-Phe⁷-α-MSH at concentrations comprised between 1 pMand 10 μm, in the presence of the compound to be tested, atconcentrations comprised between 1 nM and 10 μM in duplicate for 20minutes at 37° C.

The reaction medium is eliminated and 80 μl of lysis buffer is added.The intracellular cyclic AMP level is measured by a competition testwith fluorescent cyclic AMP (CatchPoint, Molecular Devices).

1. A compound of formula (I)

in racemic, enantiomeric form or any combinations of these forms and inwhich: A represents —C(O), —C(O)—C(R_(a))(R_(b))—; X represents —CH—;R_(a) and R_(b) represent, independently, a hydrogen atom or a(C₁-C₆)alkyl radical; R₁ represents a hydrogen atom, a (C₁-C₈)alkylradical wherein said (C₁-C₈)alkyl radical is optionally substituted byhydroxy or one or more identical or different halo radicals, a(C₂-C₆)alkenyl, or a radical of formula —(CH₂)_(n)—X₁; R₂ represents a(C₁-C₈)alkyl radical wherein said (C₁-C₈)alkyl radical is optionallysubstituted by hydroxy or one or more identical or different haloradicals, a (C₂-C₆)alkenyl, or a radical of formula —(CH₂)_(n)—X₁; eachX₁ independently represents (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, adamantyl,heterocycloalkyl, aryl, or heteroaryl, wherein the (C₃-C₇)cycloalkyl,heterocycloalkyl, aryl, and heteroaryl radicals are optionallysubstituted by one or more identical or different substituents including—(CH₂)_(n′)—V₁—Y₁, halo, nitro, cyano, or aryl; V₁ represents —O—, —S—,or a covalent bond; Y₁ represents a (C₁-C₆)alkyl radical wherein said(C₁-C₆)alkyl radical is optionally substituted by one or more identicalor different halo radicals; n represents an integer from 0 to 6 and n′an integer from 0 to 2 with the proviso that when n is equal to 0, thenX₁ does not represent the alkoxy radical; or R₁ and R₂ form togetherwith the nitrogen atom to which they are attached, a heterobicycloalkylor a heterocycloalkyl wherein said heterobicycloalkyl and saidheterocycloalkyl are independently optionally substituted by one or moreidentical or different substituents including hydroxy, (C₁-C₆)alkylwherein said (C₁-C₆)alkyl is optionally substituted by hydroxy,(C₁-C₆)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV₁′Y₁′ with V₁′ andY₁′ independently representing a hydrogen atom or a (C₁-C₆)alkyl; or R₁and R₂ together form a radical of formula:

R₃ represents -Z₃, —C(R_(Z3))(R′_(Z3))-Z₃,—C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z₃ or —C(O)-Z′₃; wherein R_(Z3) andR′_(Z3) represent, independently, a hydrogen atom or a (C₁-C₆)alkylradical; Z₃ represents Z_(3a), Z_(3b), Z_(3c), Z_(3d), or Z_(3e);wherein Z_(3a) represents a (C₁-C₆)alkyl radical; Z_(3b) represents a(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino, ordi((C₁-C₆)alkyl)amino radical; Z_(3c) represents an aryl or heteroarylradical; Z_(3d) represents a (C₁-C₆) alkoxy-carbonyl, amino-carbonyl,(C₁-C₆)alkylamino-carbonyl, di((C₁-C₆)alkyl)amino-carbonyl,(C₁-C₆)alkyl-C(O)—NH—, (C₃-C₇)cycloalkyl, or heterocycloalkyl radical;wherein the (C₃-C₇)cycloalkyl and heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents including halo, nitro, (C₁-C₆)alkoxy wherein said(C₁-C₆)alkoxy is optionally substituted by one or more identical ordifferent halo radicals, (C₁-C₆)alkyl wherein said (C₁-C₆)alkyl isoptionally substituted by one or more identical or different haloradicals, (C₁-C₆)alkyl-carbonyl, (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,(C₁-C₆)alkylamino-carbonyl, di((C-C₆)alkyl)amino-carbonyl or oxy,wherein wherein the aryl and heteroaryl radicals are optionallysubstituted by one or more identical or different substituents includinghalo, cyano, nitro, azido, oxy, (C₁-C₆)alkoxy-carbonyl-(C₁-C₆)alkenyl,(C₁-C₆)alkylamino-carbonyl-(C₁-C₆)alkenyl, —SO₂—NR₃₁R₃₂,heterocycloalkyl, heteroaryl, or —(CH₂)_(p′)—V₃—Y₃; wherein R₃₁ and R₃₂form together with the nitrogen atom to which they are attached, aheterocycloalkyl; V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —O—C(O)—,—SO₂—, —SO₂NH—, —NR₁₃—SO₂—, —NR₁₃—, —NR₁₃—C(O)—, —C(O)—NR₁₃—,—NH—C(O)—NR₁₃— or a covalent bond; Y₃ represents a hydrogen atom; a(C₁-C₆)alkyl radical optionally substituted by one or more identical ordifferent halo radicals; an aryl radical optionally substituted by oneor more identical or different substituents including halo, nitro,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or an aryl-(C₁-C₆)alkyl radical optionallysubstituted by one or more identical or different substituents includinghalo, nitro, (C₁-C₆)alkyl or (C₁-C₆)alkoxy; Z_(3e) represents a radicalof formula

Z′₃ represents an aryl radical wherein said aryl radical is optionallysubstituted by one or more identical or different substituents includinghalo, nitro, or —(CH₂)_(p″)—V′₃—Y′₃; V′₃ represents —O—, —C(O)—,—C(O)—O—, —C(O)—NR₁₃—, —NH—C(O)—NR₁₃— or a covalent bond; Y′₃ representsa hydrogen atom or a (C₁-C₆)alkyl radical wherein said (C₁₋₆)alkylradical is optionally substituted by one or more identical or differenthalo radicals; R′₃ represents a hydrogen atom, a (C₁-C₆)alkyl or(C₁-C₆)alkoxy radical; p represents an integer from 1 to 4; p′ and p″represent, independently, an integer from 0 to 4; R₄ represents aradical of formula —(CH₂)_(s)—R′₄, R′₄ represents a guanidine radical, aheterocycloalkyl containing at least one nitrogen atom wherein saidheterocycloalkyl is optionally substituted by (C₁-C₆)alkyl or aralkyl, aheteroaryl containing at least one nitrogen atom wherein said heteroarylis optionally substituted by (C₁-C₆)alkyl, or a radical of formula—NW₄W′₄; wherein, W₄ represents a hydrogen atom or (C₁-C₈)alkyl; W′₄represents a radical of formula —(CH₂)_(s′-Z) ₄; Z₄ represents ahydrogen atom, (C₁-C₈)alkyl wherein said (C₁-C₈)alkyl is optionallysubstituted by one or more identical or different substituents including(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, or hydroxy, (C₂-C₆)alkenyl,(C₃-C₇)cycloalkyl wherein said (C₃-C₇)cycloalkyl is optionallysubstituted by one or more identical or different (C₁-C₆)alkylsubstituents, cyclohexene, heteroaryl or aryl; wherein the aryl andheteroaryl radicals are optionally substituted by one or more identicalor different radicals including —(CH₂)_(s″)—V₄—Y₄, hydroxy, halo, nitroor cyano; wherein  V₄ represents —O—, —S—, —NH—C(O)—, —NV₄′— or acovalent bond;  Y₄ represents a hydrogen atom or a (C₁-C₆)alkyl radicalwherein said (C₁-C₆)alkyl radical is optionally substituted by one ormore identical or different halo radicals;  V₄′ represents a hydrogenatom or a (C₁-C₆)alkyl;  s″ represents an integer from 0 to 4; or Z₄represents a radical of formula

and s′ represent, independently, an integer from 0 to 6; with theproviso that i) when R₃ represents —C(O)-Z′₃ and R₄ represents a radicalof formula —(CH₂)_(s)—NW₄W′₄ and W₄ and W′₄ represent, independently, ahydrogen atom or a (C₁-C₆)alkyl radical, then —(CH₂)_(s) representsneither the ethylene radical nor the —(CH₂)—CH((C₁-C₄)alkyl)-radical andii) when R₃ represents -Z_(3c) and Z_(3c) represents a phenyl ornaphthyl radical, then said phenyl and naphthyl are not substituted bycyano; and it being understood that when R₃ represents -Z_(3d) thenZ_(3d) only represents one (C₃-C₇) cycloalkyl or a heterocycloalkylradical; or a pharmaceutically acceptable salt thereof. 2-5. (canceled)6. The compound of claim 1, wherein R_(a) is a methyl radical and R_(b)is a methyl radical; or a pharmaceutically acceptable salt thereof. 7.The compound of claim 6, wherein R₁ and R₂ represent, independently, a(C₁-C₈)alkyl radical; R₃ represents -Z_(3c), —C(R_(Z3))(R′_(Z3))-Z_(3c),—C(R_(Z3))(R′_(Z3))-Z_(3d) or —C(R_(Z3))(R′_(Z3))—(CH₂)_(p)-Z_(3d); R₄represents a radical of formula —(CH₂)_(s)—R₁₄; R′₄ represents aheterocycloalkyl containing at least one nitrogen atom and wherein saidheterocycloalkyl radical is optionally substituted by (C₁-C₆)alkyl, orR′₄ represents a radical of formula —NW₄W′₄ wherein W₄ represents ahydrogen atom or (C₁-C₈)alkyl; W′₄ represents a radical of formula—(CH₂)_(s′)-Z₄; Z₄ represents a hydrogen atom, the phenyl radical or aheteroaryl; s represents an integer from 2 to 4; s′ represents aninteger from 0 to 4; or a pharmaceutically acceptable salt thereof. 8.The compound of claim 7, wherein R_(Z3) and R′_(Z3) represent,independently, a hydrogen atom; Z_(3c) represents a thienyl radicaloptionally substituted by (C₁-C₆)alkoxy-carbonyl, or phenyl substitutedby one or more identical or different substituents including halo, nitroor —(CH₂)_(p′)—V₃—Y₃; wherein V₃ represents —O—, —C(O)—, —C(O)—O—,—C(O)—NR₁₃— or a covalent bond; Y₃ represents a hydrogen atom; a(C₁-C₆)alkyl radical optionally substituted by one or more identical ordifferent halo radicals; R′₃ represents a hydrogen atom; Z_(3d)represents a (C₁-C₆)alkoxy-carbonyl radical; the heterocycloalkylrepresented by R′₄ is piperidine; the heteroaryl represented by Z₄ ispyridine; or a pharmaceutically acceptable salt thereof. 9-34.(canceled)
 35. A process for preparing the compound of claim 1,comprising the step of reacting a compound of formula (II)

with an isothiocyanate of formula R₃N═C═S in the presence of a couplingagent, or yellow mercury (II) oxide in the presence of sulfur, for aperiod of 3 to 48 hours, in a protic or aprotic solvent, at atemperature of 50 to 80° C.
 36. A pharmaceutical composition comprisingat least one compound of claim 1 in combination with a pharmaceuticallyacceptable support.
 37. A method of treating pain, weight disordersmental health problems, or sexual activity disorders comprisingadministering an effective amount of the compound of claim 1 to apatient in need thereof.
 38. The method of claim 37, wherein said weightdisorders include anorexia, or cachexia.
 39. The method of claim 37wherein the method treats pain.
 40. The method of claim 37, wherein saidmethod treats mental health problems. 41-42. (canceled)
 43. A method fortreating pain, weight disorders, mental health problems, or sexualactivity disorders, comprising the step of administering to a patient inneed thereof an effective amount of a compound of claim
 1. 44. Themethod of claim 43, wherein R₁ and R₂ is, independently, a (C₁-C₈)alkyl;R₃ is Z_(3c) and Z_(3c) is a phenyl or naphthyl, wherein the phenyl orthe napthyl are substituted by at least one cyano; R₄ is —(CH₂)_(s)—R′₄wherein R′₄ is a pyrrolidinyl or piperidinyl; or —NW₄W′₄ wherein W₄ is ahydrogen atom or a (C₁-C₈)alkyl; and W′₄ is —(CH₂)₈—H; wherein s is aninteger from 2 to 4 and s′ is an integer from 0 to 4; or apharmaceutically acceptable salt thereof.
 45. The method of claim 38,wherein said weight disorder is cancer cachexia, AIDS cachexia, old-agecachexia, cardiac cachexia, renal cachexia, or cachexia in rheumatoidarthritis.
 46. The method of claim 38, wherein the method treatsneuropathic pain.
 47. The method of claim 39, wherein said mental healthproblems include anxiety or depression.